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Journal Cover European Journal of Medical Genetics
  [SJR: 0.814]   [H-I: 35]   [6 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1769-7212
   Published by Elsevier Homepage  [2969 journals]
  • Duplications of SLC1A3: Associated with ADHD and autism
    • Abstract: Publication date: Available online 11 June 2016
      Source:European Journal of Medical Genetics
      Author(s): Claudia J.M. van Amen-Hellebrekers, Sandra Jansen, Rolph Pfundt, Janneke H. Schuurs-Hoeijmakers, David A. Koolen, Carlo L. Marcelis, Nicole de Leeuw, Bert B.A. de Vries
      We report four patients with a similar gain in 5p13.2 encompassing a single gene: SLC1A3. Behavioural problems resembling ADHD and/or autism-like features are observed which is in line with the glial glutamate transporter role of SLC1A3. We consider an association between SLC1A3 and the behavioural problems which can also be considered a contributing factor to behavioural problems in larger duplications overlapping the 5p13 microduplication syndrome region.


      PubDate: 2016-06-13T18:20:45Z
       
  • Two male sibs with severe micrognathia and a missense variant in MED12
    • Abstract: Publication date: Available online 7 June 2016
      Source:European Journal of Medical Genetics
      Author(s): Trine E. Prescott, Mari Ann Kulseth, Ketil R. Heimdal, Barbro Stadheim, Einar Hopp, Tomek Gambin, Zeynep H. Coban Akdemir, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Gibbs, James R. Lupski, Asbjørg Stray-Pedersen
      Missense variants in MED12 cause three partially overlapping dysmorphic X-linked intellectual disability (XLID) syndromes: Lujan-Fryns syndrome (also known as Lujan syndrome), FG syndrome (also known as Opitz-Kaveggia syndrome) and X-linked Ohdo syndrome. We report a family with two severely micrognathic male sibs, a 10½ year old boy and a fetus, in which hemizygosity for a previously unreported missense variant in exon 13 of MED12 (NM_005120.2), c.1862G > A, p.(Arg621Gln) was detected by whole exome sequencing. The affected sibs shared no other rare variant with relevance to the phenotype. X-chromosome inactivation in blood was completely skewed (100:0) in the unaffected heterozygous mother, most likely as a result of preferential inactivation of the X-chromosome harbouring the missense variant in MED12. Neither the unaffected brother nor the unaffected maternal grandfather carried the missense variant in MED12. In the 10½ year old boy, upper airway obstruction secondary to Pierre Robin sequence necessitated a tracheostomy for the first 10 months of life. He has mild to moderate intellectual disability and some dysmorphic features seen in MED12-related syndromes. In addition, he has a horizontal gaze paresis, anomalies of the inner ear, and a cervical block vertebra. This report contributes to the expanding phenotypic range associated with MED12-mutations.


      PubDate: 2016-06-08T18:04:12Z
       
  • A novel SMARCAL1 missense mutation that affects splicing in a severely
           affected Schimke immunoosseous dysplasia patient
    • Abstract: Publication date: Available online 6 June 2016
      Source:European Journal of Medical Genetics
      Author(s): Jimena Barraza-García, Carlos I. Rivera-Pedroza, Alberta Belinchón, Carlota Fernández-Camblor, Blanca Valenciano-Fuente, Pablo Lapunzina, Karen E. Heath
      Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive disease characterized by skeletal dysplasia, focal segmental glomerulosclerosis, renal failure and immunodeficiency. In this work, we report the molecular studies undertaken in a severely affected SIOD patient that died at six years old due to nephropathy. The patient was screened for mutations using a targeted skeletal dysplasias panel. A homozygous novel missense mutation was identified, c.1615C > G (p.[Leu539Val]) that was predicted as mildly pathogenic by in silico pathogenicity prediction tools. However, splicing prediction software suggested that this variant may create a new splicing donor site in exon 9, which was subsequently confirmed using a minigene assay in HEK293 cells. Thus, the splicing alteration, c.1615C > G; r.1615c > g, 1615_1644del; (p.[Leu539_Ile548del]), results in the loss of 10 amino acids of the HARP-ATPase catalytic domain and the RPA-binding domain. Several studies have demonstrated a weak genotype-phenotype correlation among such patients. Thus, the molecular characterization has helped us to understand why a predicted weakly pathogenic missense mutation results in severe SIOD and should be considered in similar scenarios.


      PubDate: 2016-06-08T18:04:12Z
       
  • MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and
           review
    • Abstract: Publication date: Available online 31 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Helena Rocha, Mafalda Sampaio, Ruben Rocha, Susana Fernandes, Miguel Leão
      Introduction MEF2C haploinsufficiency syndrome is characterized by severe intellectual disability, epilepsy, stereotypic movements, minor dysmorphisms and brain abnormalities. We report the case of a patient with a new MEF2C mutation, comparing his clinical and imaging features to those previously reported in the literature. Case report A 10 year-old boy first came to pediatric neurology clinic at the age of 11 months because of severe psychomotor delay, without regression. He presented generalized hypotonia, poor eye contact, hand-mouth stereotypies, strabismus and minor facial dimorphisms. Epileptic seizures started at 26 months of age and were refractory. Brain MRI showed a slight increase in periventricular white matter signal and globally enlarged CSF spaces. Molecular analysis revealed a de novo, pathogenic and causative MEF2C mutation. Discussion MEF2C haploinsufficiency syndrome was recently recognized as a neurodevelopmental disorder. Severe intellectual disability with inability to speak and epilepsy are universal features in patients with MEF2C mutations, although mild cognitive and speech disorders have been reported to occur in patients with duplications. Epilepsy might be absent in patients with partial deletions. Abnormal movement patterns are very common in patients with MEF2C haploinsufficiency. Delayed myelination seems to be more commonly observed in patients with MEF2C mutations, while malformations of cortical development were only reported in patients with microdeletions. Although MEF2C haploinsufficiency prevalence is yet to be determined, it should be considered in the differential diagnosis of patients with severe intellectual disability and Rett-like features.


      PubDate: 2016-06-03T17:50:13Z
       
  • The molecular characterization of beta globin gene in thalassemia patients
           reveals rare and a novel mutations in Pakistani population.
    • Abstract: Publication date: Available online 1 June 2016
      Source:European Journal of Medical Genetics
      Author(s): Humaira Yasmeen, Sarmad Toma, Natalie Killeen, Shahida Hasnain, Letizia Foroni
      Introduction A multicentre study (including four cities in Pakistan) aimed to investigate the frequency and spectrum of alpha and beta thalassemia genetic mutations and XmnI polymorphism of the Gamma Globin gene. Methods One hundred and sixty one beta thalassemia patients, identified on the ground of haematological parameters, were screened for mutations of the Alpha (HBA2 and HBA1) and Beta (HBB) Globin genes as well as Gamma (HBG2) Globin gene XmnI polymorphism using a combination of multiplex GAP polymerase chain reaction (PCR), Sanger sequencing and restriction fragment length polymerase (RFLP) based PCR. Results Mutations of at least one HBB gene was identified in 157 of 161 patients screened. Among 16 identified mutations in the beta gene, HBB:c.27_28insG (p. Ser10Valfs*14) was the most prevalent. α−3.7 and α−4.2 deletions were co-inherited with beta thalassemia mutations. Rare mutations such as HBB:c.–138C > T and HBB:c.315 + 1G > A were also identified. One novel variant (HBB:c.–148T > A), two rare mutations [HBB:c.332T > C (p.Leu111Pro); HBB:c.92G > C (p.Arg31Thr] and a novel association, HBB:c.[92G > C (p.Arg31Thr)] and [-92C > G], were reported for the first time in our study. HBG2:c.–211C > T base-pair substitution (historically described as -158 GγXmnI polymorphism) was present in 36% of the patients. Conclusion Heterogeneity in clinical and haematological parameters in TM, show that monogenic disorders can present with a wide spectrum of disease severity. Our studies identified rare and novel mutations that will be useful in the prevention of highly prevalent disease of thalassemia in Pakistan following nationwide awareness campaign.


      PubDate: 2016-06-03T17:50:13Z
       
  • Analysis of tissue from products of conception and perinatal losses using
           QF-PCR and microarray: A three-year retrospective study resulting in an
           efficient protocol
    • Abstract: Publication date: Available online 24 May 2016
      Source:European Journal of Medical Genetics
      Author(s): K. Wou, Y. Hyun, D. Chitayat, M. Vlasschaert, K. Chong, S. Wasim, S. Keating, P. Shannon, E. Kolomietz
      Objective To evaluate the performance of a laboratory protocol for direct genetic analysis performed on tissues obtained from miscarriages, stillbirth and postnatal death. Methods Samples were collected between July 1st, 2011 and June 30th, 2014. QF-PCR analysis was the initial test followed by aCGH analysis performed on the normal QF-PCR specimens. Results Of the 1195 submitted specimens, a total of 1071 samples were confirmed as true fetal. The failure rate was 1.4%. Of those, 30.8% yielded abnormal results. Of the latter, 57.6% had abnormal QF-PCR and 42.4% had abnormal microarray result. Autosomal trisomies were detected in 61.2%, triploidy in 7.6%, monosomy X in 9.1%, sex-chromosome aneuploidy (apart from monosomy X) in 1.5%, molar pregnancies in 5.8% and copy number variants in 14.2% including microdeletions/microduplications and cryptic unbalanced rearrangements. The highest diagnostic yield was observed in the 1st trimester specimens at 67.6%. We confirmed that maternal age correlates with the likelihood of autosomal trisomies but not with triploidy, sex chromosome aneuploidies, molar pregnancy, or CNVs. Conclusion An efficient laboratory protocol, based on QF-PCR and aCGH of uncultured cells has replaced standard cytogenetic analysis in testing of tissue from all pregnancy losses in our center and resulted in reduced test failure rate and increased diagnostic yield.


      PubDate: 2016-05-29T17:40:35Z
       
  • Multiple giant cell lesions in a patient with Noonan syndrome with
           multiple lentigines
    • Abstract: Publication date: Available online 26 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Henk van den Berg, Willem Hans Schreuder, Marjolijn Jongmans, Danielle van Bommel-Slee, Bart Witsenburg, Jan de Lange
      A patient with Noonan syndrome with multiple lentigines (NSML) and multiple giant cell lesions (MGCL) in mandibles and maxillae is described. A mutation p.Thr468Met in the PTPN11-gene was found. This is the second reported NSML patient with MGCL. Our case adds to the assumption that, despite a different molecular pathogenesis and effect on the RAS/MEK pathway, NSML shares the development of MGCL, with other RASopathies.


      PubDate: 2016-05-29T17:40:35Z
       
  • Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum
           disorder
    • Abstract: Publication date: Available online 27 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Gifty Bhat, Danielle LaGrave, Alison Millson, John Herriges, Allen N. Lamb, Reuben Matalon
      We report an 8-year-old female with autism spectrum disorder (ASD), intellectual disability and speech delay who was found to carry a de novo 82 kb deletion of chromosome Xq11.1-11.2 involving the ARHGEF9 gene on chromosomal microarray. So far, 11 patients with point mutations, disruptions due to chromosomal rearrangements and deletions involving ARHGEF9 have been reported in the literature. ARHGEF9-related disorders comprise a wide phenotypic spectrum, including behavior disorders, autism spectrum disorder, intellectual disability, hyperekplexia and infantile epileptic encephalopathy. ARHGEF9 encodes for collybistin which plays an important role in post synaptic clustering of glycine and inhibitory gamma-aminobutyric acid receptors along with its scaffolding partner, gephyrin. The reduction of inhibitory receptor clusters in brain has been proposed as a plausible underlying pathophysiological mechanism. With this report, we provide further evidence for the role of ARHGEF9 in neurocognitive function, its implication in ASD, and review the clinical features of previously published individuals with ARHGEF9-related intellectual disability.


      PubDate: 2016-05-29T17:40:35Z
       
  • Treatment of acute leukemia in children with ataxia telangiectasia (A-T)
    • Abstract: Publication date: Available online 27 May 2016
      Source:European Journal of Medical Genetics
      Author(s): M.H.D. Schoenaker, F. Suarez, T. Szczepanski, N. Mahlaoui, J.L. Loeffen
      Early onset ataxia telangiectasia (A-T) is a neurodegenerative DNA-instability disorder, which presents early in childhood. Hallmarks of A-T are progressive ataxia and a dramatic increased risk of developing malignancies (25%), especially of hematological origin. In children these malignancies mainly concern aggressive Non-Hodgkin lymphoma, acute leukemias and Hodgkin lymphoma. Of the acute leukemias, T-cell lymphoblastic leukemia (T-ALL) is by far the most common. Since patients with A-T experience increased toxicity to radio- and chemotherapeutic treatment, the optimal treatment strategy of acute leukemia remains subject of debate. Review of literature of treatment of T-ALL in patients with A-T (n = 18) showed that many patients are not diagnosed with A-T at time of presentation of T-ALL. This implicates that physicians must be aware of symptoms of A-T in young patients presenting with T-ALL. Complete remission rates are high following upfront modified as well as unmodified treatment strategies. Treatment of ALL in children with A-T is feasible and should be performed. Definitive treatment strategy must be determined by shared decision making with patient, caretakers and medical team. Future prospective studies are needed to elucidate optimal treatment strategy.


      PubDate: 2016-05-29T17:40:35Z
       
  • A case report of hereditary apolipoprotein A-I amyloidosis associated with
           a novel APOA1 mutation and variable phenotype
    • Abstract: Publication date: Available online 27 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Birgitte G. Tougaard, Katja Venborg Pedersen, Søren Rasmus Palmelund Krag, Janet A. Gilbertson, Dorota Rowczenio, Julian D. Gillmore, Henrik Birn
      Apolipoprotein A-I (apo A-I) amyloidosis is a non-AL, non-AA, and non-transthyretin type of amyloidosis associated with mutations in the APOA1 gene inherited in an autosomal dominant fashion. It is a form of systemic amyloidosis, but at presentation, can also mimic localized amyloidosis. The renal presentation generally involves interstitial and medullary deposition of apo A-I amyloid protein. We describe the identification of apo A-I amyloidosis by mass spectrometry in a 52-year old male, with no family history of amyloidosis, presenting with nephrotic syndrome and associated with heterozygosity for a novel APOA1 mutation (c.220 T > A) which encodes the known amyloidogenic Trp50Arg variant. Renal amyloid deposits in this case were confined to the glomeruli alone, and the patient developed progressive renal impairment. One year after diagnosis, the patient had a successful kidney transplant from an unrelated donor. Pathogenic mutations in the APOA1 gene are generally associated with symptoms of amyloidosis. In this family however, genotyping of family members identified several unaffected carriers suggesting a variable disease penetrance, which has not been described before in this form of amyloidosis and has implications when counselling those with APOA1 mutations.


      PubDate: 2016-05-29T17:40:35Z
       
  • A novel frameshift mutation of DDHD1 in a Japanese patient with autosomal
           recessive spastic paraplegia
    • Abstract: Publication date: Available online 20 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Shiroh Miura, Takuya Morikawa, Ryuta Fujioka, Kengo Kosaka, Kohei Yamada, Gohsuke Hattori, Manabu Motomura, Takayuki Taniwaki, Hiroki Shibata
      Spastic paraplegia (SPG) type 28 is an autosomal recessive SPG caused by mutations in the DDHD1 gene. We examined a Japanese 54-years-old male patient with autosomal recessive SPG. His parents were consanguineous. He needed a wheelchair for transfer due to spastic paraplegia. There was a history of operations for bilateral hallux valgus, thoracic ossification of the yellow ligament, bilateral carpal tunnel syndrome, bilateral ankle contracture, and lumbar spinal canal stenosis. He noticed gait disturbance at age 14. He used a cane for walking in his 40s. On neurological examination, he showed hyperreflexia, spasticity, and weakness in the lower extremities and bilateral Babinski reflexes. Urinary dysfunctions and impaired vibration sense in the lower limbs were observed. By exome sequencing analysis using Agilent SureSelect and Illumina MiSeq, we identified 17,248 homozygous nucleotide variants in the patient. Through the examination of 48 candidate genes known to be responsible for autosomal recessive SPG, we identified a novel homozygous 4-bp deletion, c.914_917delGTAA, p.Ser305Ilefs*2 in exon2 of the DDHD1 gene encoding phosphatidic acid-preferring phospholipase A1 (PA-PLA1). The mutation is expected to cause a frameshift generating a premature stop codon 3-bp downstream from the deletion. In consequence, the DDHD domain that is known to be critical for PLA1 activity is completely depleted in the mutated DDHD1 protein, predicted to be a functionally null mutation of the DDHD1 gene. By Sanger sequencing, we confirmed that both parents are heterozygous for the mutation. This variation was not detected in 474 Japanese control subjects as well as the data of the 1,000G Project. We conclude that the novel mutation in DDHD1 is the causative variant for the SPG28 patient that is the first record of the disease in Japanese population.


      PubDate: 2016-05-23T17:26:04Z
       
  • Angelman syndrome in Hong Kong Chinese: A 20 years’ experience
    • Abstract: Publication date: June 2016
      Source:European Journal of Medical Genetics, Volume 59, Issues 6–7
      Author(s): H.M. Luk, Ivan F.M. Lo
      AS(OMIM #105830) is a neurodevelopmental disease that characterized by severe intellectual disability, lack of speech, happy disposition, ataxia, epilepsy and distinct behavioural profile. A tertiary wide study was performed in Hong Kong with aim to examine the clinical and molecular features, genotype-phenotype correlation of the Angelman syndrome (AS) patients. There were total 55 molecularly confirmed AS between January 1995 to September 2015 for review. 65.5% of them were caused by maternal microdeletion, 10.9% by paternal uniparental disomy, 3.6% by imprinting center defect and 14.5% by UBE3A gene mutation. Genotype-phenotype correlation showed epilepsy and microcephaly is more common in microdeletion type as compared with non-microdeletional type. We have concluded that the incidence rate, clinical features and underlying genetic mechanisms in Hong Kong Chinese were comparable with other western populations. The overall average age of diagnosis in this cohort was 6.2 years old (95% C.I was 5.0–7.5 years old). It is hope that by increasing awareness and early referral could result in early diagnosis and better management for AS patient.


      PubDate: 2016-05-14T15:43:27Z
       
  • Chromosome Xq28 duplication encompassing MECP2: Clinical and molecular
           analysis of 16 new patients from 10 families in China
    • Abstract: Publication date: Available online 11 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Zhi Yi, Hong Pan, Lin Li, Hairong Wu, Songtao Wang, Yinan Ma, Yu Qi
      Introduction Chromosome Xq28 duplications encompassing methyl-CpG-binding protein 2 gene (MECP2) are observed most in males with a severe neurodevelopmental disorder associated with hypotonia, spasticity, severe learning disability, delayed psychomotor development, and recurrent pulmonary infections. Most female carriers are asymptomatic due to extremely or completely skewed X-inactivation. Methods A retrospective clinical and molecular study was conducted to examine 16 patients and two fetuses from 10 families who were identified among patients with Xq28 duplications who presented at genetic clinics. Results Of all 16 patients, 10 had a family history. Only one patient was female. All of the patients had no relevant pre-natal history. All of the patients exhibited severe psychomotor developmental delay, infantile hypotonia and recurrent infections. Some of the patients exhibited cardiac abnormalities, gastrointestinal mobility problems, hydrocele of tunica vaginalis, cryptorchidism, and autistic phenotypes. Additionally, neonatal kidney calculus, premature closure of the fontanel and pulmonary sequestration were found in the patients. Duplication sizes in these patients range from 0.21 to 14.391 Mb (most were smaller than 1 Mb), and all the duplications included host cell factor C1 (HCFC1), interleukin-1 receptor-associated kinase 1 (IRAK1), and MECP2. Bioinformatics analysis revealed that approximately half of the distal breakpoints were located within the low-copy repeats (LCRs), which may be involved in the recombination. The two fetuses were found to be healthy in the prenatal diagnosis. Conclusion This is the first large cohort of patients with MECP2 duplication syndrome, including a female, reported in China. Interestingly, neonatal kidney calculus, premature closure of the fontanel and pulmonary sequestration were first reported in this syndrome. However, it was difficult to distinguish if these patients represented unique cases or if these phenotypes can be considered as part of the syndrome. The correlation between the infrequent phenotypes and duplications/genes in the duplication region needs further systematic delineation. In conclusion, our study suggested that it is important to emphasize molecular genetic analysis in patients with developmental delay/intellectual disability and recurrent infections and that it is especially important for familial female carriers to accept prenatal diagnosis.


      PubDate: 2016-05-14T15:43:27Z
       
  • A novel nonsense GPSM2 mutation in a Yemeni family underlying
           Chudley-McCullough syndrome.
    • Abstract: Publication date: Available online 11 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Abdul Rezzak Hamzeh, Pratibha Nair, Madiha Mohamed, Fatima Saif, Nafisa Tawfiq, Mahmoud Taleb Al-Ali, Fatma Bastaki
      Mutations in the G Protein Signaling Modulator 2 (GPSM2) cause the autosomal recessive disorder Chudley-McCullough syndrome (CMS), which is characterized by profound congenital sensorineural hearing loss with various abnormalities in the brain. This phenotypic combination is attributed to the role played by GPSM2 in the establishment of planar polarity and spindle orientation during asymmetric cell divisions. Here we present two brothers from a Yemeni family who were diagnosed clinically with CMS then tested for GPSM2 mutations using Sanger sequencing. Consequent to sequencing, in silico tools (such as CADD) were utilized to assess functional consequences. Molecular analysis revealed a previously unreported homozygous mutation in GPSM2 in both brothers (c.1055C > A) leading to a truncating protein change; (p.Ser352*). This mutation is predicted to abolish all four GoLoco domains in GPSM2 and this explains the bioinformatic prediction for this mutation to be functionally damaging. Full clinical and molecular accounts of the novel mutation are provided in this paper.


      PubDate: 2016-05-14T15:43:27Z
       
  • Identification of novel mutations in CD2BP1 gene in clinically proven
           rheumatoid arthritis patients of south India
    • Abstract: Publication date: Available online 13 May 2016
      Source:European Journal of Medical Genetics
      Author(s): B. Siddhartha Kumar, P. Santhosh Kumar, N. Sowgandhi, B. Manoj Prajwal, A. Mohan, K.V.S. Sarma, P.V.G.K. Sarma
      Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA syndrome) is a rare autosomal dominant, auto-inflammatory disease that affects joints and skin. The disease results due to mutations in the cluster of differentiation 2 binding protein 1 (CD2BP1) gene on chromosome 15q24.3. Rheumatoid arthritis (RA) is a common, genetically complex disease that affects the joints with occasional skin manifestations. Studies related to the pathophysiology of inflammation in these two disorders show a certain degree of overlap at genetic level. The present study was done to confirm the existence of such a genetic overlap between PAPA syndrome and RA in south Indian population. In the present study 100 patients who were clinically diagnosed rheumatoid arthritis and 100 apparently healthy controls were chosen and the 15 exons of CD2BP1 gene were PCR-amplified and sequenced. The sequence analysis showed that in exon 3 thirty eight patients revealed presence of novel heterozygous missense mutations p.Glu51Asp, p.Leu57Arg and p.Ala64Thr. In exons 6, 10 and 14 eight patients showed 44 novel missense mutations and two patients showed novel frame shift mutations p.(Met123_Leu416delinsThr) and p.(Thr337Profs*52) leading to truncated protein formation. Such mutations were not seen in controls. Further, the in silico analysis revealed the mutant CD2BP1 structure showed deletion of Cdc15 and SH3 domains when superimposed with the wild type CD2BP1 structure with variable RMSD values. Therefore, these structural variations in CD2BP1 gene due to the mutations could be one of the strongest reasons to demonstrate the involvement of these gene variations in the patients with rheumatoid arthritis.


      PubDate: 2016-05-14T15:43:27Z
       
  • Two patients with chromosome 22q11.2 deletion presenting with childhood
           obesity and hyperphagia
    • Abstract: Publication date: Available online 13 May 2016
      Source:European Journal of Medical Genetics
      Author(s): J.K. Bassett, K.E. Chandler, S. Douzgou
      Chromosome 22q11.2 deletion syndrome is a clinically heterogeneous condition of intellectual disability, parathyroid and thyroid hypoplasia, palatal abnormalities, cardiac malformations and psychiatric symptoms. Hyperphagia and childhood obesity is widely reported in Prader-Willi Syndrome (PWS) but there is only one previous report of this presentation in chromosome 22q11.2 deletion syndrome. We describe two further cases of chromosome 22q11.2 deletion syndrome in which hyperphagia and childhood obesity were the presenting features. This may be a manifestation of obsessive behaviour secondary to some of the psychiatric features commonly seen in chromosome 22q11.2 deletion syndrome. Serious complications may result from hyperphagia and childhood obesity therefore early recognition and intervention is crucial. Due to the similar clinical presentation of these two patients to patients with PWS, it is suggested that the hyperphagia seen here should be managed in a similar way to how it is managed in PWS.


      PubDate: 2016-05-14T15:43:27Z
       
  • A novel ACVR1 mutation detected by whole exome sequencing in a family with
           an unusual skeletal dysplasia
    • Abstract: Publication date: Available online 13 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Maryam Rafati, Faezeh Mohamadhashem, Azadeh Hoseini, Fatemeh Hoseininasab, Saeed RezaGhaffari
      “Disorganized Development of Skeletal Component” (DDSC) is a group of genetic skeletal dysplasia, caused by mutations in 9 genes including ACVR1. The most known ACVR1-related disorder is fibrodysplasia ossificans progressiva (FOP). FOP variants are frequently encountered with diagnostic challenges due to overlapping clinical manifestations and variable severity. Application of high throughput sequencing methods can overcome these limitations by simultaneous investigation of the entire ACVR1 gene together with other genes involved in disorders with similar manifestations. A 33-year-old man with an unusual skeletal dysplasia and no previous clinical diagnosis is presented in this study. Whole exome sequencing detected a novel c.737T>A (p.Phe246Tyr) mutation in ACVR1 gene. Detailed targeted variant analysis in 226 known genes associated with genetic skeletal disorders together with more specific targeted analysis in 9 genes associated with DDSC ruled out the involvement of other investigated genes. Proband's phenotypically normal father and brother had the same mutation in whom subsequent investigations showed subclinical radiographic findings. The clinical manifestations, the disease course, and the molecular findings of involvement of ACVR1 gene in this family are suggestive of “FOP variant” or an unusual ACVR1-related skeletal dysplasia. Moreover, this report has demonstrated the critical role of the next generation sequencing technique in characterizing such a rare disorder with variable and even no clinical manifestations, providing the opportunity for effective preventive measures such as preimplantation genetic diagnosis.


      PubDate: 2016-05-14T15:43:27Z
       
  • A novel mutation in FBXL4 in a Norwegian child with encephalomyopathic
           mitochondrial DNA depletion syndrome 13
    • Abstract: Publication date: Available online 13 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Tuva Barøy, Christeen Ramane J. Pedurupillay, Yngve T. Bliksrud, Magnhild Rasmussen, Asbjørn Holmgren, Magnus D. Vigeland, Timothy Hughes, Maaike Brink, Richard, Bård Nedregaard, Petter Strømme, Eirik Frengen, Doriana Misceo
      Mitochondrial DNA depletion syndromes (MTDPS) represent a clinically and genetically heterogeneous group of autosomal recessive disorders, caused by mutations in genes involved in maintenance of mitochondrial DNA (mtDNA). Biallelic mutations in FBXL4 were recently described to cause encephalomyopathic MTDPS13. The syndrome has infantile onset and presents with hypotonia, feeding difficulties, a pattern of mild facial dysmorphisms, global developmental delay and brain atrophy. Laboratory investigations reveal elevated blood lactate levels, unspecific mitochondrial respiratory chain (MRC) enzyme deficiencies and mtDNA depletion. We report a novel missense variant, c.1442T > C (p.Leu481Pro), in FBXL4 (NM_012160.4) in a Norwegian boy with clinical, biochemical and cerebral MRI characteristics consistent with MTDPS13. The FBXL4 c.1442T > C (p.Leu481Pro) variant was not present in public databases, 149 Norwegian controls nor an in-house database containing whole exome sequencing data from 440 individuals, and it was predicted in silico to be deleterious to the protein function. Activities of MRC enzymes were normal in muscle tissue (complexes I–IV) and cultured skin fibroblasts (complexes I–V) from the patient, but mtDNA depletion was confirmed in muscle, thus supporting the predicted pathogenicity of the FBXL4 c.1442T > C (p.Leu481Pro) variant. On clinical indication of mitochondrial encephalomyopathy, sequencing of FBXL4 should be performed, even when the activity levels of the MRC enzymes are normal.


      PubDate: 2016-05-14T15:43:27Z
       
  • Update of the spectrum of GJB2 gene mutations in 152 Moroccan families
           with autosomal recessive nonsyndromic hearing loss
    • Abstract: Publication date: Available online 8 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Amina Bakhchane, Amale Bousfiha, Hicham Charoute, Sara Salime, Mustapha Detsouli, Khalid Snoussi, Sellama Nadifi, Mostafa Kabine, Hassan Rouba, Hind Dehbi, Rachida Roky, Majida Charif, Abdelhamid Barakat
      Deafness is one of the most common genetic diseases in humans and is subject to important genetic heterogeneity. The most common cause of non syndromic hearing loss (NSHL) is mutations in the GJB2 gene. This study aims to update and evaluate the spectrum of GJB2 allele variants in 152 Moroccan multiplex families with non syndromic hearing loss. Seven different mutations were detected: c.35delG, p.V37I, p.E47X, p.G200R, p.Del120E, p.R75Q, the last three mutations were described for the first time in Moroccan deaf patients, in addition to a novel nonsense mutation, the c.385G˃T which is not referenced in any database. Sixty six families (43.42%) have mutations in the coding region of GJB2, while the homozygous c.35delG mutation still to date the most represented 51/152 (33.55%). The analysis of the geographical distribution of mutations located in GJB2 gene showed more allelic heterogeneity in the north and center compared to the south of Morocco. Our results showed that the GJB2 gene is a major contributor to non syndromic hearing loss in Morocco. Thus, this report of the GJB2 mutations spectrum all over Morocco has an important implication for establishing a suitable molecular diagnosis.


      PubDate: 2016-05-09T14:20:00Z
       
  • Spectrum of clinical manifestations in two young Turkish patients with
           congenital generalized lipodystrophy type 4
    • Abstract: Publication date: Available online 7 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Gulcin Akinci, Haluk Topaloglu, Baris Akinci, Huseyin Onay, Cem Karadeniz, Yakup Ergul, Tevfik Demir, Emin Evren Ozcan, Canan Altay, Tahir Atik, Abhimanyu Garg
      Congenital generalized lipodystrophy type 4 is an extremely rare autosomal recessive disorder. We report our clinical experience on two unrelated Turkish patients with congenital generalized lipodystrophy type 4. A 13-year-old girl (patient-1) presented with generalized lipodystrophy and myopathy. Further tests revealed ventricular and supraventricular arrhythmias, gastrointestinal dysmotility, atlantoaxial instability, lumbosacral scoliosis, and metabolic abnormalities associated with insulin resistance. A 16-year-old girl (patient-2) with congenital generalized lipodystrophy type 4 was previously reported. Here, we report on her long term clinical follow-up. She received several course of anti-arrhythmic treatments for catecholaminergic polymorphic ventricular tachycardia and rapid atrial fibrillation. An implantable cardioverter defibrillator was also placed. A homozygous PTRF mutation, c.259C > T (p.Gln87*), was identified in patient-1. Congenital generalized lipodystrophy type 4 was caused by homozygous PTRF c.481-482insGTGA (p.Lys161Serfs*41) mutation in patient-2. Our data indicate that patients with congenital generalized lipodystrophy type 4 should be meticulously evaluated for cardiac, neuromuscular, gastrointestinal and skeletal diseases, as well as metabolic abnormalities associated with insulin resistance.


      PubDate: 2016-05-09T14:20:00Z
       
  • A template for broad consent in biobank research. Results and explanation
           of an evidence and consensus-based development process
    • Abstract: Publication date: Available online 26 April 2016
      Source:European Journal of Medical Genetics
      Author(s): D. Strech, S. Bein, M. Brumhard, W. Eisenmenger, C. Glinicke, T. Herbst, R. Jahns, S. von Kielmansegg, G. Schmidt, J. Taupitz, H.D. Tröger
      Background Biobanks increasingly presume long-term storage of biomaterials and data that shall be used for future research projects which are today unspecified. Appropriate consent documents for sample donors must therefore explain the breadth of consent and other elements of the biobank governance framework. Recent reviews demonstrated high variability in what issues these documents mention or not and how the issues are explained. This might undermine the protection of sample donors, complicate networked biobank research, create research waste and impact on public trust. Methods A systematic analysis of international research guidelines and existing broad consent templates was performed. Based on this information an interdisciplinary expert group from the AKMEK (Permanent Working Party of German RECs) developed a draft template and organized a comprehensive stakeholder consultation. After revision the final template was consented by all 53 German RECs. Results This paper briefly explores the spectrum of potentially relevant issues for broad consent forms. It then elaborates the template and how it was designed to be applicable in different types of biobanks. Discussion To further improve the validity and applicability of broad consent forms in biobank and other big data research, practice evaluations are needed. We hope that in this regard the presented template supports the development of new consent forms as well as the evaluation and revision of existing ones.


      PubDate: 2016-04-30T14:26:26Z
       
  • Partial deletion of TCF4 in three generation family with non-syndromic
           intellectual disability, without features of Pitt-Hopkins syndrome
    • Abstract: Publication date: Available online 28 April 2016
      Source:European Journal of Medical Genetics
      Author(s): Mira Kharbanda, Kaja Kannike, Anne Lampe, Jonathan Berg, Tõnis Timmusk, Mari Sepp
      Mutations in TCF4 (basic helix-loop-helix transcription factor 4), a gene with complex organization and multiple transcription initiation sites, are usually associated with Pitt-Hopkins syndrome (PTHS). However, a translocation encompassing the 5′ end of TCF4 and several point mutations have been linked to non-syndromic intellectual disability (NSID). Here we describe a family with autosomal dominantly inherited NSID in seven relatives with a partial deletion of TCF4, disrupting the 5′ end of the gene, predicted to result in the reduction of the number of mRNAs that can be produced by alternative transcription initiation. Functional studies indicate that it leads to reduced levels of transcripts coding for TCF4 protein isoforms with a nuclear localization signal, which may be relevant to the phenotype. The findings in our family support the notion that the position of the mutation in TCF4 is relevant to the phenotype, with those mutations in the 5′ region, cassette exons and regions not affecting the important functional domains being linked to NSID rather than PTHS. We suggest that screening for mutations in TCF4 could be considered in the investigation of NSID.


      PubDate: 2016-04-30T14:26:26Z
       
  • Progressive osseous heteroplasia is not a Mendelian trait but a type 2
           segmental manifestation of GNAS inactivation disorders: A hypothesis
    • Abstract: Publication date: Available online 4 April 2016
      Source:European Journal of Medical Genetics
      Author(s): Rudolf Happle
      Progressive osseous heteroplasia (POH) is a segmental disorder characterized by progeressive heterotopic ossification that extends from dermal and subcutaneous tissues to deeper structures. So far, it has been taken as a rarely occurring bone disease with autosomal dominant inheritance. Here, arguments are presented in favor of the alternative concept that the disorder is merely a type 2 segmental manifestation of autosomal dominant GNAS inactivation disorders. Type 2 segmental mosaicism arises, in a heterozygous embryo, from a somatic mutational event that occurs at an early developmental stage, resulting in loss of the corresponding wild-type allele and giving rise to a homozygous or hemizygous cell clone. As a characteristic feature, such type 2 segmental involvement is far more pronounced than the type 1 segmental mosaicism as noted in otherwise healthy individuals. The concept of type 2 segmental mosaicism has been proven at the molecular level in six human traits including neurofibromatosis 1, Hailey-Hailey disease, and Gorlin syndrome. In POH, molecular proof of principle is so far lacking. The following lines of reasoning, however, support the hypothesis that POH can be explained by a similar mechanism. Firstly, POH has been found to be associated with different phenotypes caused by inactivating GNAS mutations, which is why it cannot be categorized as one distinct Mendelian trait. Secondly, POH occurs as a rather rare complication of these autosomal dominant traits, which is not compatible with the assumption of a separate Mendelian disorder. Thirdly, in a case of plate-like osteoma that represents a more superficial variant of POH, molecular proof of the concept of type 2 segmental manifestation has already been provided, and the available literature suggests that POH can be best explained by a similar mechanism. Moreover, findings obtained in animal experiments support the assumption that human POH represents such superimposed segmental manifestation of GNAS inactivation disorders.


      PubDate: 2016-04-09T07:21:03Z
       
  • Neoplasia in Turner syndrome. The importance of clinical and screening
           practices during follow-up
    • Abstract: Publication date: Available online 4 April 2016
      Source:European Journal of Medical Genetics
      Author(s): Daniela Larizza, Michela Albanesi, Annalisa De Silvestri, Giulia Accordino, Valeria Brazzelli, Gabriella Carnevale Maffè, Valeria Calcaterra
      Aim of the study Turmer syndrome (TS) patients show increased morbidity due to metabolic, autoimmune and cardiovascular disorders. A risk of neoplasia is also reported. Here, we review the prevalence of neoplasia in a cohort of Turner patients. Methods We retrospectively evaluated 87 TS women. Follow-up included periodic ultrasound of the neck, abdominal and pelvic organs, dermatologic evaluation and fecal occult blood test. Karyotype was 45,X in 46 patients. During follow-up, 63 girls were treated with growth hormone, 65 with estro-progestin replacement therapy and 20 with L-thyroxine. Autoimmune diseases were present in 29 TS. Results A total of 17 neoplasms in 14 out of 87 patients were found. Six skin neoplasia, 3 central nervous system tumors, 3 gonadal neoplasia, 2 breast tumors, 1 hepatocarcinoma, 1 carcinoma of the pancreas and 1 follicular thyroid cancer were detected. Age at tumor diagnosis was higher in 45,X pts than in those with other karyotypes (p=0.003). Adenomioma gallbladdder (AG) was detected in 15.3% of the patients, with a lower age in girls at diagnosis with an associated neoplasia in comparison with TS without tumors (p=0.017). No correlation between genetic make up, treatment, associated autoimmune diseases and neoplastia was found. Conclusion In our TS population an increased neoplasia prevalence was reported. A high prevalence of AG was also noted and it might be indicative of a predisposition to neoplasia. Further studies are needed to define the overall risk for neoplasia, and to determine the role of the loss of the X-chromosome and hormonal therapies.


      PubDate: 2016-04-09T07:21:03Z
       
  • A novel Xq22.1 deletion in a male with multiple congenital abnormalities
           and respiratory failure
    • Abstract: Publication date: Available online 16 March 2016
      Source:European Journal of Medical Genetics
      Author(s): Yang Cao, Umut Aypar
      Here we report the first male case of a novel Xq22.1 deletion. An 8-week-old boy with multiple congenital abnormalities and respiratory failure was referred to the Mayo Clinic Cytogenetics laboratory for testing. Chromosomal microarray analysis identified a novel 1.1 Mb deletion at Xq22.1. A similar deletion has only been described once in the literature in a female patient and her mother; both have intellectual disability and dysmorphic facial features. In addition, the mother had a son who died at 15 days due to breathing failure. Recently, a mouse model revealed that a 0.35 Mb sub-region, containing 4 genes, is sufficient to cause majority of the Xq22.1 deletion phenotypes. The deleted intervals in our male patient and the female patients contain 15 common genes, including the four described in the 0.35 Mb sub-region. Male mice with deletion of the 0.35 Mb sub-region died perinatally from respiratory failure due to pulmonary hypoplasia, consistent with the breathing problem and potential neonatal fatality in male patients. The phenotypes of the mouse models and the patients are strikingly similar; therefore, the deletion of these five genes (ARMCX5, ARMCX5-GPRASP2, GPRASP1, GPRASP2, and BHLHB9) is likely responsible for the novel Xq22.1 deletion syndrome.


      PubDate: 2016-03-20T13:53:25Z
       
  • A neurocutaneous phenotype with paired hypo- and hyperpigmented macules,
           microcephaly and stunted growth as prominent features
    • Abstract: Publication date: Available online 12 March 2016
      Source:European Journal of Medical Genetics
      Author(s): Piero Pavone, Andrea Domenico Praticò, Giulia Gentile, Raffaele Falsaperla, Rosario Iemmolo, Maria Guarnaccia, Sebastiano Cavallaro, Martino Ruggieri
      Neurocutaneous disorders represent a heterogeneous group of conditions affecting the skin (with pigmentary/vascular abnormalities, hamartomas or tumors) and the central and peripheral nervous systems. In recent years, besides the well-known neurocutaneous diseases (e.g., the different forms of neurofibromatosis, tuberous sclerosis complex, Sturge-Weber syndrome and mosaic pigmentary/hamartomatous disorders), new distinctive syndromes have been characterized, extending our knowledge on the spectrum of these conditions. The concurrent presence of pigmentary abnormalities (both of the hypo- and hyperpigmented type), and primary microcephaly has not been commonly reported.


      PubDate: 2016-03-15T12:38:15Z
       
  • Genetic predisposition and hematopoietic malignancies in children: Primary
           Immunodeficiency
    • Abstract: Publication date: Available online 11 March 2016
      Source:European Journal of Medical Genetics
      Author(s): Jutte van der Werff ten Bosch, Machiel van den Akker
      It is assumed that patients with some forms of primary immunodeficiency (PID) have a markedly increased risk of cancer as compared to the healthy population. This increased incidence is seen in children as well as adult patients. The type of malignancy depends on the underlying genetic defect, but hematopoietic cancers are most frequent in almost any subtype of PID. In some patients, a malignancy can even be the first or only symptom of an underlying genetic defect. The possibility of an underlying PID is important for the pediatric oncologist as this might influence the treatment. Also, patients with a known PID should be screened for the occurrence of cancer. It is therefore important to raise awareness on this subject among clinicians involved in the treatment of children with cancer as well as in the treatment of children with PID.


      PubDate: 2016-03-11T12:17:45Z
       
  • FOCAL CORTICAL DYSPLASIA, MICROCEPHALY AND EPILEPSY IN A BOY WITH
           1q21.1-q21.3 DUPLICATION
    • Abstract: Publication date: Available online 11 March 2016
      Source:European Journal of Medical Genetics
      Author(s): Roberta Milone, Angelo Valetto, Roberta Battini, Veronica Bertini, Giulia Valvo, Giovanni Cioni, Federico Sicca
      The recent advance of new molecular technologies like array - Comparative Genomic Hybridization has fostered the detection of genomic imbalances in subjects with intellectual disability, epilepsy, and/or congenital anomalies. Though some of the rearrangements are relatively frequent, their consequences on phenotypes can be strongly variable. We report on a boy harbouring a de novo 8.3 Mb duplication of chromosome 1q21.1-q21.3 whose complex unusual phenotype deserves attention, due to the presence of focal cortical dysplasia, microcephaly, and epilepsy. Loss-of-function (LOF) effects of genes associated with human disease involved in the rearrangement have been only partially established, and have not been previously associated with brain malformations in several deletion syndromes. Less is known, instead, about the consequences of their duplication on neuronal migration and brain development process. Further advance in neuroimaging and genetic research will help in defining their actual role in neurodevelopment and cerebral cortex malformations.


      PubDate: 2016-03-11T12:17:45Z
       
  • CHD8 intragenic deletion associated with autism spectrum disorder
    • Abstract: Publication date: Available online 26 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Elliot S. Stolerman, Brooke Smith, Alka Chaubey, Julie R. Jones
      Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that are highly heritable. De novo genomic alterations are considered an important cause of autism spectrum disorders. Recent research has shown that de novo loss-of-function mutations in the chromodomain helicase DNA-binding protein 8 (CHD8) gene are associated with an increased risk of ASD. We describe a single case of an intragenic deletion of exons 26-28 in the CHD8 gene in a patient with autism and global developmental delay. Our clinical case supports the hypothesis that CHD8 may play a central role in neuronal cell development and ASD risk.


      PubDate: 2016-02-29T10:57:47Z
       
  • Genetics of Human Isolated Acromesomelic Dysplasia
    • Abstract: Publication date: Available online 27 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Saadullah Khan, Sulman Basit, Muzammil Ahmed Khan, Noor Muhammad, Wasim Ahmad
      Acromesomelic dysplasia is a type of skeletal malformation affecting distal and middle segments of the extremities. It occurs in both isolated (non-syndromic) and syndromic forms. In later case, it shows association with cardiac, respiratory, neurological and genital abnormalities. Acromesomelic dysplasia segregates in autosomal recessive mode of inheritance. Mutations in three genes (GDF5, NPR2, BMPR1B) have been reported to cause different forms of acromesomelic dysplasia. In the present review we have discussed clinical spectrum, genetics and signalopathies of isolated acromesomelic dysplasias.


      PubDate: 2016-02-29T10:57:47Z
       
  • A new familial case of microdeletion syndrome 10p15.3
    • Abstract: Publication date: Available online 24 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Marlene Eggert, Stefan Müller, Uwe Heinrich, Yasmin Mehraein
      In 2012 a small terminal deletion in the short arm of chromosome 10 in the region 10p15.3 was reported as a novel microdeletion syndrome. By now 21 patients, including a single familial case, have been reported. Characteristic findings comprise variable cognitive impairment or developmental delay, disorder of speech development, as well as various dysmorphic signs. We here report on a new patient, an eight year old girl, with a microdeletion syndrome 10p15.3. She is a foster child showing intellectual deficits, disorder of speech development, behavioral problems, congenital heart defect, and several dysmorphic signs. The same microdeletion was subsequently found in the six year old maternal half-sister, showing very similar developmental and cognitive issues, including major speech impairment. The mother has not obtained a school degree. She was described as being a dissocial person with severe alcohol abuse and showing minor cognitive disability. Thus inheritance of the microdeletion from a probably symptomatic mother can be assumed. The patients presented here add up to the as yet small number of reported cases of microdeletion 10p15.3 and thereby might help to establish a more comprehensive clinical spectrum of this rather newly discovered syndrome.


      PubDate: 2016-02-25T10:14:52Z
       
  • The use of two different MLPA kits in 22q11.2 Deletion Syndrome
    • Abstract: Publication date: Available online 24 February 2016
      Source:European Journal of Medical Genetics
      Author(s): L.J.M. Evers, J.J.M. Engelen, L.M.H. Houben, L.M.G. Curfs, T.A.M.J. van Amelsvoort
      22q11.2 deletion syndrome (22q11DS) is one of the most common recurrent copy-number variant disorder, caused by a microdeletion in chromosome band 22q11.2 and occurring with a population prevalence of 1 in 2000. Until today there has been no evidence that the size of the deletion has an influence on the clinical phenotype. Most studies report that 22q11DS is associated with mild or borderline intellectual disability. There are a limited number of reports on 22q11DS subjects with moderate or severe intellectual disability. In this study we describe 63 adult patients with 22q11DS, including 22q11DS patients functioning at a moderate to severe intellectual disabled level. Deletion size was established with an experimental Multiplex ligation-dependent probe amplification (MLPA) mixture (P324) in addition to the commonly used MLPA kit (P250). We compared deletion size with intellectual functioning and presence of psychotic symptoms during life. The use of the experimental MLPA kit gives extra information on deletion size, only when combined with the common MLPA kit. We were able to detect eleven atypical deletions and in two cases the deletion size was shorter than all other “typical ones”. We conclude that the use of the experimental kit P324 gives extra information about the deletion size, but only when used together with the standard P250 kit. We did not found any relation of deletion size with intelligence or presence of psychosis.


      PubDate: 2016-02-25T10:14:52Z
       
  • A novel homozygous splice site mutation in NALCN identified in siblings
           with Cachexia, Strabismus, Severe Intellectual Disability, Epilepsy and
           Abnormal Respiratory Rhythm
    • Abstract: Publication date: Available online 23 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Moran Gal, Daniella Magen, Younan Zahran, Ayelet Eran, Morad Khayat, Chen Gafni, Erez Y. Levanon, Hanna Mandel
      We studied three siblings, born to consanguineous parents who presented with severe intellectual disability, cachexia, strabismus, seizures and episodes of abnormal respiratory rhythm. Whole exome sequencing led to identification of a novel homozygous splice site mutation, IVS29-1G>A in the NALCN gene, that resulted in aberrant transcript in the patients. NALCN encodes a voltage-independent cation channel, involved in regulation of neuronal excitability. Three homozygous mutations in the NALCN gene were previously identified in only eight patients with severe hypotonia, speech impairment, cognitive delay, constipation and Infantile–Neuroaxonal-dystrophy- like symptoms. Our patients broaden the clinical spectrum associated with recessive mutations in NALCN, featuring also disrupted respiratory rhythm mimicking homozygous Nalcn knockout mice.


      PubDate: 2016-02-25T10:14:52Z
       
  • A case of mild CHARGE syndrome associated with a splice site mutation in
           CHD7
    • Abstract: Publication date: Available online 24 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Constance Wells, Natalie Loundon, Noel Garabedian, Sylvette Wiener-Vacher, Marie-Dominique Cordier-Bouvier, Géraldine Goudeffroye, Tania Attie-Bitach, Sandrine Marlin
      CHARGE syndrome (MIM#214800) (Coloboma, Heart defect, Atresia of choanae, Retarded growth and development, Genital hypoplasia, Ear abnormalities/deafness) is caused by heterozygous mutation of CHD7 transmitted in an autosomal dominant manner. In this report, we describe a patient with bilateral hearing impairment, unusually-shaped ears, no intellectual disability and a patent ductus arteriosus. Further investigation showed abnormal semicircular canals and the presence of olfactory bulbs. He does not fulfill the Blake or the Verloes criteria for CHARGE. A de novo mutation at the donor splice site of intron 33 was identified (c.7164+1G>A). It is of importance to diagnose mildly affected patients for appropriate genetic counselling and to better understand the mild end of the phenotypic spectrum of CHARGE syndrome.


      PubDate: 2016-02-25T10:14:52Z
       
  • Immunoglobulin K Light Chain Deficiency: a rare, but probably
           underestimated, humoral immune defect
    • Abstract: Publication date: Available online 4 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Pierguido Sala, Antonio Colatutto, Dora Fabbro, Laura Mariuzzi, Stefania Marzinotto, Barbara Toffoletto, Anna R. Perosa, Giuseppe Damante
      Human immunoglobulin molecules are generated by a pair of identical heavy chains, which identify the immunoglobulin class, and a pair of identical light chains, Kappa or Lambda alternatively, which characterize the immunoglobulin type. In normal conditions, Kappa light chains represent approximately 2/3 of the light chains of total immunoglobulins, both circulating and lymphocyte surface bound. Very few cases of immunoglobulin Kappa or Lambda light chain defects have been reported. Furthermore, the genetic basis of this defect has been extensively explored only in a single case. We report a case of a patient suffering of serious recurrent bacterial infections, which was caused by a very rare form of immunoglobulin disorder, consisting of a pure defect of Kappa light chain. We evaluated major serum immunoglobulin concentrations, as well as total and free Kappa and Lambda light chain concentrations. Lymphocyte phenotyping was also performed and finally we tested the Kappa chain VJ rearrangement as well as the constant Kappa region sequence. Studies performed on VJ rearrangement showed a polyclonal genetic arrangement, whereas the gene sequencing for the constant region of Kappa chain showed a homozygous T to G substitution at the position 1288 (rs200765148). This mutation causes a substitution from Cys to Gly in the protein sequence and, therefore, determines the abnormal folding of the constant region of Kappa chain. We suggest that this defect could lead to an effective reduction of the variability of total antibody repertoire and a consequent defect of an apparently normal immunoglobulin response to common antigens.


      PubDate: 2016-02-12T11:02:47Z
       
  • Seven novel mutations of the SMPD1 gene in four Chinese patients with
           Niemann-Pick disease type A and prenatal diagnosis for four fetuses
    • Abstract: Publication date: Available online 4 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Yuan Ding, Xiyuan Li, Yupeng Liu, Ying Hua, Jinqing Song, Liwen Wang, Mengqiu Li, Yaping Qin, Yanling Yang
      Background Niemann-Pick disease type A (NPD-A) is a rare autosomal recessive lysosomal storage disorder caused by acid sphingomyelinase deficiency. Only a few cases have been documented in mainland China, and prenatal diagnosis has not been performed to date. In this study, the clinical and laboratory features of four Chinese patients with early-onset NPD-A were summarized. Methods Four patients with NPD-A were the firstborns of non-consanguineous parents from four unrelated Chinese families. Bone marrow analysis, acid sphingomyelinase assay and genetic studies were performed. SMPD1 gene studies on amniocytes were performed for the prenatal diagnosis of four fetuses from three families. Results Four patients were admitted at the age of 1 to 10 months due to jaundice, hepatosplenomegaly and psychomotor retardation. Liver histopathological analysis revealed glucolipid accumulation. Massive foamy histiocytes were found in the bone marrow. Acid sphingomyelinase activities of peripheral blood leukocytes were significantly decreased (4.05 to 21.9 nmol/h/mg protein, normal range 216.1 to 950.9 nmol/h/mg protein). Seven novel mutations (c.518-519insT, c.562_563insC, c.792Gdel, c.949G>A, c.1487_1499delACCGTGTGTACCA, c.1495T>C and c.1670T>C) of the SMPD1 gene were identified in four patients. Only one fetus had two mutations of the SMPD1 gene of amniocytes. The results suggested that the fetus was affected by NPD-A. The mother chose artificial abortion. The other three fetuses were not affected by NPD-A. No mutation of the SMPD1 gene was detected in the cultured amniocytes from the mothers. Postnatal genetic analysis and normal development of the three infants confirmed the prenatal diagnosis. Conclusions Seven novel mutations associated with NPD-A were identified in the Chinese population. Prenatal diagnosis for four fetuses of three families was successfully performed by amniocyte gene analysis.


      PubDate: 2016-02-12T11:02:47Z
       
  • Maternally inherited autosomal dominant intellectual disability caused by
           16p13.3 microduplication
    • Abstract: Publication date: Available online 9 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Cha Gon Lee, Eunhae Cho, Young-min An
      A 16p13.3 duplication syndrome has been recently suggested to be a novel recognizable syndrome as a reciprocal microduplication disease of Rubinstein-Taybi syndrome. The CREBBP gene is believed to be the dosage-sensitive critical gene responsible for the reciprocal duplication and deletion syndrome. Descriptions so far have been de novo. Here, we report a very rare case of a maternally inherited a -1Mb sized duplication on 16p13.3 identified by SNP array testing. The patient showed moderate intellectual disability, normal growth, and characteristic facial features. The patient’s mother also had mild intellectual disability, normal growth, camptodactyly, proximally implanted small thumbs, and distinctive facial features. The study provides additional information that furthers the understanding and delineation of 16p13.3 duplication syndrome.


      PubDate: 2016-02-12T11:02:47Z
       
  • Neonatal Severe Hyperparathyroidism caused by homozygous mutation in CASR:
           A Rare Cause of Life-Threatening Hypercalcemia
    • Abstract: Publication date: Available online 6 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Heidi Murphy, Jessica Patrick, Eileen Báez-Irizarry, Yves Lacassie, Ricardo Gómez, Alfonso Vargas, Brian Barkemeyer, Sohit Kanotra, Regina M. Zambrano
      Neonatal severe hyperparathyroidism (NSHPT) is a rare, life-threatening condition that presents with severe hypercalcemia, hyperparathyroidism, and osteopenia in the newborn period. Treatment of NSHPT traditionally includes hydration and bisphosphonates; however newer calcimimetic agents, such as cinacalcet, are now being utilized to prevent or delay parathyroidectomy which is technically difficult in the newborn. Medical treatment success is related to calcium sensing receptor (CaSR) genotype. We report a 4-day-old infant who presented with hyperbilirubinemia, poor feeding, weight loss, severe hypotonia and was ultimately diagnosed with NSHPT. The patient’s total serum calcium level of 36.8 mg/dL (reference range: 8.5-10.4 mg/dL) is, to our knowledge, the highest ever documented in this setting. Exome data previously obtained on the infant’s parents was re-analyzed demonstrating bi-parental heterozygosity for a mutation of the CASR gene: c.206G>A, and Sanger sequencing data confirmed the patient was a homozygote for the same mutation. Though a patient with the same CaSR gene mutation described here has responded to cinacalcet, our patient did not respond and required parathyroidectomy. Though this case has previously been published as a surgical case report, a full report of the medical management and underlying genetic etiology is warranted; this case underscores the importance of disclosing bi-parental heterozygosity for a gene causing severe neonatal disease particularly when treatment is available and illustrates the need for further in vitro studies of this CaSR mutation.


      PubDate: 2016-02-12T11:02:47Z
       
  • Incomplete penetrance of biallelic ALDH1A3 mutations
    • Abstract: Publication date: Available online 10 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Julie Plaisancié, Dominique Brémond-Gignac, Bénédicte Demeer, Véronique Gaston, Alain Verloes, Lucas Fares-Taie, Sylvie Gerber, Jean-Michel Rozet, Patrick Calvas, Nicolas Chassaing
      The formation of a properly shaped eye is a complex developmental event that requires the coordination of many induction processes and differentiation pathways. Microphthalmia and anophthalmia (MA) represent the most severe defects that can affect the ocular globe during embryonic development. When genetic, these ocular disorders exhibit large genetic heterogeneity and extreme variable expressivity. Around 20 monogenic diseases are known to be associated with MA as main phenotype and the penetrance of mutations is usually full in the patients. Some of these genes encode proteins involved in the vitamin A pathway, tightly regulated during eye development. One of those retinoic acid synthesis genes is ALDH1A3 and biallelic mutations in that gene have been recently found to lead to MA phenotype in patients. Interestingly, we report here the lack of ocular defect in a girl carrying the same homozygous mutation in the ALDH1A3 gene than the affected members of her family. Thus, this report brings new information for the phenotype-genotype correlation of ALDH1A3 mutations and raises important questions, especially in terms of genetic counselling given to the patients and their families. Furthermore, these data contribute to the more general understanding that we have for the complex genetic inheritance of these MA phenotypes.


      PubDate: 2016-02-12T11:02:47Z
       
  • Pre- and post-natal growth in two sisters with 3-M syndrome
    • Abstract: Publication date: Available online 2 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Licia Lugli, Emma Bertucci, Vincenzo Mazza, Amira Elmakky, Fabrizio Ferrari, Christine Neuhaus, Antonio Percesepe
      3-M syndrome (OMIM #273750) is a rare autosomal recessive growth disorder characterized by severe pre- and post-natal growth restriction, associated with minor skeletal abnormalities and dysmorphisms. Although the 3-M syndrome is well known as a primordial dwarfism, descriptions of the prenatal growth are missing. We report a family with variable phenotypic features of 3-M syndrome and we describe the prenatal and postnatal growth pattern of two affected sisters with a novel homozygous CUL7 mutation (c.3173-1G>C), showing a pre- and post-natal growth deficiency and a normal cranial circumference.


      PubDate: 2016-02-12T11:02:47Z
       
  • Somatic mosaicism of the PIK3CA gene identified in a Hungarian girl with
           macrodactyly and syndactyly
    • Abstract: Publication date: Available online 3 February 2016
      Source:European Journal of Medical Genetics
      Author(s): Kornélia Tripolszki, Rachel Knox, Victoria Parker, Robert Semple, Katalin Farkas, Adrien Sulák, Emese Horváth, Márta Széll, Nikoletta Nagy
      Isolated macrodactyly (OMIM 155500) belongs to a heterogeneous group of overgrowth syndromes. It is a congenital anomaly resulting in enlargement of all tissues localized to the terminal portions of a limb and caused by somatic mutations in the phosphatidylinositol 3-kinase catalytic alpha (PIK3CA, OMIM 171834) gene. Here we report a Hungarian girl with macrodactyly and syndactyly. Genetic screening at hotspots in the PIK3CA gene identified a mosaic mutation (c.1624G > A, p.Glu542Lys) in the affected tissue, but not in the peripheral blood. To date, this somatic mutation has been reported in eight patients affected by different forms of segmental overgrowth syndromes. Detailed analysis of the Hungarian child and previously reported cases suggests high phenotypic diversity associated with the p.Glu542Lys somatic mutation. The identification of the mutation provides a novel therapeutic modality for the affected patients: those who carry somatic mutations in the PIK3CA gene are potential recipients of a novel “repurposing” approach of rapamycin treatment.


      PubDate: 2016-02-12T11:02:47Z
       
  • A structured assessment of motor function and behavior in patients with
           Kleefstra Syndrome
    • Abstract: Publication date: Available online 22 January 2016
      Source:European Journal of Medical Genetics
      Author(s): Susanne Schmidt, Heidi E. Nag, Bente S. Hunn, Gunnar Houge, Lise B. Hoxmark
      The present study aimed to further our understanding of Kleefstra syndrome, especially regarding motor function and behavioral characteristics. In total, four males and four females between two and 27 years of age with a genetically confirmed diagnosis of Kleefstra syndrome and their parents participated in this study. Four patients had 9q34.3 deletions that caused Euchromatin Histone Methyl Transferase 1 (EHMT1) haplo-insufficiency, and four patients harbored EHMT1 mutations. The motor function was evaluated via systematic observation. Standardized assessments such as the Vineland Adapted Behavior Scales II (VABS II), the Social Communication Questionnaire (SCQ) and the Child or Adult Behavior Checklist (CBCL, ABCL) were used for the behavioral assessment. All patients showed a delayed developmental status. Muscular hypotonia and its manifestations were present in all patients, regardless of their age. The mean values for all VABS II domains (communication, socialization, daily living skills, and motor skills) were significantly lower than the mean of the reference population (p < 0.001), but similar to other rare intellectual disabilities such as Smith-Magenis syndrome and Angelman syndrome. The results from the SCQ indicated that all patient values exceeded the cut-off value, suggesting the possibility of autism spectrum disorder. The behavioral and emotional problems assessed by CBCL and ABCL were less frequent. In conclusion, patients with Kleefstra syndrome present with a broad range of clinical problems in all age groups and are therefore in need of a multidisciplinary follow-up also after their transition into adulthood.


      PubDate: 2016-01-28T00:56:01Z
       
  • Clinical course and therapeutic implications for lymphoid malignancies in
           Nijmegen breakage syndrome
    • Abstract: Publication date: Available online 27 January 2016
      Source:European Journal of Medical Genetics
      Author(s): Agata Pastorczak, Tomasz Szczepanski, Wojciech Mlynarski
      Nijmegen breakage syndrome (NBS, MIM #251260) is an autosomal recessive chromosomal instability disorder. Majority of patients affected are of Slavic origin and share the same founder mutation of 657del5 within the NBN gene encoding protein involved in DNA double-strand breaks repair. Clinically, this is characterized by a microcephaly, immunodeficiency and a high incidence of pediatric malignancies, mostly lymphomas and leukemias. Anticancer treatment among patients with NBS is challenging because of a high risk of life threatening therapy-related toxicity including severe infections, bone marrow failure, cardio- and nephrotoxicity and occurrence of secondary cancer. Based on systemic review of available literature and the Polish acute lymphoblastic leukemia database we concluded that among patients with NBS, these who suffered from clinically proven severe immunodeficiency are at risk of the complications associated with oncological treatment. Thus, in this group it reasonable to reduce chemotherapy up to 50% especially concerning anthracyclines methotrexate, alkylating agents and epipodophyllotoxines, bleomycin and radiotherapy should be omitted. Moreover, infection prophylaxis using intravenous immunoglobulin supplementation together with antifungal and antibacterial agent is recommended. To replace radiotherapy or some toxic anticancer agents targeted therapy using monoclonal antibodies and kinase inhibitors or bone marrow transplantation with reduced-intensity conditioning should be considered in some cases, however, this statement needs further studies.


      PubDate: 2016-01-28T00:56:01Z
       
  • Recognition of genetic predisposition in pediatric cancer patients: An
           easy-to-use selection tool
    • Abstract: Publication date: Available online 26 January 2016
      Source:European Journal of Medical Genetics
      Author(s): Marjolijn C.J. Jongmans, Jan L.C.M. Loeffen, Esmé Waanders, Peter M. Hoogerbrugge, Marjolijn J.L. Ligtenberg, Roland P. Kuiper, Nicoline Hoogerbrugge
      Genetic predisposition for childhood cancer is under diagnosed. Identifying these patients may lead to therapy adjustments in case of syndrome-related increased toxicity or resistant disease and syndrome-specific screening programs may lead to early detection of a further independent malignancy. Cancer surveillance might also be warranted for affected relatives and detection of a genetic mutation can allow for reproductive counseling. Here we present an easy-to-use selection tool, based on a systematic review of pediatric cancer predisposing syndromes, to identify patients who may benefit from genetic counseling. The selection tool involves five questions concerning family history, the type of malignancy, multiple primary malignancies, specific features and excessive toxicity, which results in the selection of those patients that may benefit from referral to a clinical geneticist.


      PubDate: 2016-01-28T00:56:01Z
       
  • Novel VIPAS39 Mutation in a Syndromic Patient with Arthrogryposis, Renal
           Tubular Dysfunction and Intrahepatic Cholestasis
    • Abstract: Publication date: Available online 23 January 2016
      Source:European Journal of Medical Genetics
      Author(s): Majid Aflatounian, Holly Smith, Fatemeh Farahani, Azam Tofighi Naeem, Anna Straatman-Iwanowska, Samaneh Zoghi, Urvi Khatri, Parisa Tajdini, Gholam Hossein Fallahi, Paul Gissen, Nima Rezaei
      ARC syndrome is a rare autosomal recessive disease, characterized by arthrogryposis, renal tubular dysfunction and cholestasis. Herein a 2.5 month old infant with dysmorphic features, including small anterior fontanel, low set ears, beaked nose and high arched palate is presented who was referred because of icterus. He also suffered from some additional anomalies, including unilateral choanal atresia, club foot, and bilateral developmental dislocation of hip, while further studies showed renal tubular acidosis and hearing impairment in addition to cholestasis. Genetic studies showed a homozygous mutation in the VIPAS39 gene. Making the definite diagnosis of the syndrome is important, while increased risk of mutation in other siblings highlights the importance of prenatal diagnosis.


      PubDate: 2016-01-28T00:56:01Z
       
 
 
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