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The impact of epigenomic Next Generation Sequencing approaches on our understanding of neuropsychiatric disorders.
ger V Abstract Patients suffering from psychiatric disorders have a life span burden, which represents an enormous human, family, social, and economical cost. Several concepts have revolutionized our way of appraising neuropsychiatric disorders (NPDs). They result from a combination of genetic factors and environmental insults, and their etiology finds roots in the neurodevelopmental period. As epigenetic mechanisms tightly control brain development, exposure to adverse conditions disturbing the epigenetic landscape of the fetal brain increases the risk of developing NPDs, due to the persistence of abnormal epigen...
Source: Clinical Genetics - July 11, 2017 Category: Genetics & Stem Cells Authors: Schang AL, Sabéran-Djoneidi D, Mezger V Tags: Clin Genet Source Type: research

Clinical Experience with a Single-Nucleotide Polymorphism-Based Noninvasive Prenatal Test for Five Clinically Significant Microdeletions.
Abstract Single-nucleotide polymorphism (SNP)-based noninvasive prenatal testing (NIPT) can currently predict a subset of submicroscopic abnormalities associated with severe clinical manifestations. We retrospectively analyzed the performance of SNP-based NIPT in 80,449 referrals for 22q11.2 deletion syndrome and 42,326 referrals for 1p36, cri-du-chat, Prader-Willi, and Angelman microdeletion syndromes over a one-year period, and compared the original screening protocol with a revision that reflexively sequenced high-risk calls at a higher depth of read. The prevalence of these microdeletion syndromes was also est...
Source: Clinical Genetics - July 11, 2017 Category: Genetics & Stem Cells Authors: Martin K, Iyengar S, Kalyan A, Lan C, Simon AL, Stosic M, Kobara K, Ravi H, Truong T, Ryan A, Demko ZP, Benn P Tags: Clin Genet Source Type: research

Phenotypic spectrum associated with de novo mutations in QRICH1 gene.
Abstract Rare de novo mutations represent a significant cause of idiopathic developmental delay. The use of NGS has boosted the identification of de novo mutations in an increasing number of novel genes. Here we present three unrelated children with de novo LoF mutations in QRICH1, diagnosed through trio exome sequencing. QRICH1 encodes the glutamine-rich protein 1, which contains one Caspase Activation Recruitment Domain and is likely to be involved in apoptosis and inflammation. All three children had speech delay, learning difficulties, a prominent nose and a thin upper lip. In addition, two of them had mildly ...
Source: Clinical Genetics - July 10, 2017 Category: Genetics & Stem Cells Authors: Ververi A, Splitt M, Dean J, DDD study, Brady A Tags: Clin Genet Source Type: research

Genotype-phenotype study in patients with VCP valosin-containing protein mutations associated with multisystem proteinopathy.
Abstract Mutations in valosin-containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males, 113 females) from 36 families carrying 15 different VCP mutations. We analyzed correlation between the different mutations and prevalence, age of onset and severity of myopathy, PDB, and FTD, and other comorbidities. Myopathy, PDB and FT...
Source: Clinical Genetics - July 10, 2017 Category: Genetics & Stem Cells Authors: Al-Obeidi E, Al-Tahan S, Surampalli A, Goyal N, Wang A, Hermann A, Omizo M, Smith C, Mozaffar T, Kimonis V Tags: Clin Genet Source Type: research

Homozygosity for a missense variant in COMP gene associated with severe pseudoachondroplasia.
r J Abstract The phenotypic spectrum associated with heterozygous mutations in cartilage oligomeric matrix protein gene (COMP) range from a mild form of multiple epiphyseal dysplasia (MED) to pseudoachondroplasia (PSACH). However, the phenotypic effect from biallelic COMP variants is unclear. We investigated a large consanguineous Pakistani family with a severe form of PSACH in two individuals. Another 14 family members presented with a mild PSACH phenotype similar to MED. Using exome sequencing and subsequent segregation analysis, we identified homozygosity for a COMP missense variant (c.1423G>A; p.(D475N)) in...
Source: Clinical Genetics - July 7, 2017 Category: Genetics & Stem Cells Authors: Tariq M, Khan TN, Lundin L, Jameel M, Lönnerholm T, Baig SM, Dahl N, Klar J Tags: Clin Genet Source Type: research

Integrated Analysis of SNP, CNV and Gene Expression Data in Genetic Association Studies.
We present different methods to compare this gene list with the other three possible lists that result from the combinations of the following pairs of data: SNP genotype with gene expression, CNV genotype with gene expression, and SNP genotype with CNV genotype. The comparison is done using three different cancer datasets and two different methods of comparison. Our results show that integrating SNP, CNV, and gene expression data give better association results than integrating any pair of three data. PMID: 28685831 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - July 7, 2017 Category: Genetics & Stem Cells Authors: Momtaz R, Ghanem NM, El-Makky NM, Ismail MA Tags: Clin Genet Source Type: research

Genetic characterization of GSD I in Serbian population revealed unexpectedly high incidence of GSD Ib and three novel SLC37A4 variants.
Abstract Glycogen storage disease (GSD) type I is inborn metabolic disease characterized by accumulation of glycogen in multiple organs. We analyzed 38 patients with clinical suspicion of GSD I using Sanger and next-generation sequencing (NGS). We identified 28 GSD Ib and five Ia patients. In five patients, GSD III, VI, IX, cholesteryl-ester storage disease and Shwachman-Diamond syndrome diagnoses were set using NGS. Incidences for GSD Ia and GSD Ib were estimated at 1:172746 and 1:60461 live-births respectively. Two variants were identified in G6PC gene: c.247C>T (p.Arg83Cys) and c.518T>C (p.Leu173Pro). In ...
Source: Clinical Genetics - July 7, 2017 Category: Genetics & Stem Cells Authors: Skakic A, Djordjevic M, Sarajlija A, Klaassen K, Tosic N, Kecman B, Ugrin M, Spasovski V, Pavlovic S, Stojiljkovic M Tags: Clin Genet Source Type: research

Mining for mitochondrial mechanisms: linking known syndromes to mitochondrial function.
Abstract Mitochondrial disorders (MDs) are caused by defects in one or multiple complexes of the oxidative phosphorylation (OXPHOS) machinery. MDs are associated with a broad range of clinical signs and symptoms, and have considerable clinical overlap with other neuromuscular syndromes. This overlap might be due to involvement of mitochondrial pathways in some of these non-mitochondrial syndromes. Here, we give an overview of around 25 non-mitochondrial syndromes, diagnosed in patients who were initially suspected to have a MD on the basis of clinical and biochemical parameters. In addition, we highlight the mitoc...
Source: Clinical Genetics - July 7, 2017 Category: Genetics & Stem Cells Authors: Panneman DM, Smeitink JA, Rodenburg RJ Tags: Clin Genet Source Type: research

NDUFA9 point mutations cause a variable mitochondrial complex I assembly defect.
ns LG Abstract Mitochondrial respiratory chain complex I consists of 44 different subunits and contains three functional modules: the Q-, the N- and the P-module. NDUFA9 is a Q-module subunit required for complex I assembly or stability. However, its role in complex I biogenesis has not been studied in patient fibroblasts. So far, a single patient carrying an NDUFA9 variant with a severe neonatally fatal phenotype has been reported. Via exome sequencing, we identified a novel homozygous NDUFA9 missense variant in another patient with a milder phenotype including childhood-onset progressive generalized dystonia and...
Source: Clinical Genetics - July 3, 2017 Category: Genetics & Stem Cells Authors: Baertling F, Sánchez-Caballero L, van den Brand MA, Fung CW, Chan SH, Wong VC, Hellebrekers DME, de Coo IFM, Smeitink JA, Rodenburg RJ, Nijtmans LG Tags: Clin Genet Source Type: research

Protein misfolding diseases: prospects of pharmacological treatment.
erdá C, Pérez B Abstract Protein misfolding has been linked to numerous inherited diseases. Loss- and gain-of-function mutations (common features of genetic diseases) may cause the destabilization of proteins, leading to alterations in their properties and/or cellular location, resulting in their incorrect functioning. Misfolded proteins can, however, be rescued via the use of proteostasis regulators and/or pharmacological chaperones, suggesting that treatments with small molecules might be developed for a range of genetic diseases. This work describes the potential of these small molecules in this r...
Source: Clinical Genetics - July 3, 2017 Category: Genetics & Stem Cells Authors: Gámez A, Yuste-Checa P, Brasil S, Briso-Montiano Á, Desviat LR, Ugarte M, Pérez-Cerdá C, Pérez B Tags: Clin Genet Source Type: research

Phenotypic spectrum of mutations in IBA57, a candidate gene for cavitating leukoencephalopathy.
This study provided more information about the natural history and evolution of neuroimaging. Combined with previously reported patient studies, our findings suggest that defects in IBA57 can produce diverse phenotypes. IBA57 should be considered a candidate gene for cavitating leukoencephalopathy. PMID: 28671726 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - July 3, 2017 Category: Genetics & Stem Cells Authors: Liu M, Zhang J, Zhang Z, Zhou L, Jiang Y, Wang J, Xiao J, Wu Y Tags: Clin Genet Source Type: research

Next generation phenotyping in Emanuel and Pallister Killian Syndrome using computer-aided facial dysmorphology analysis of 2D photos.
Abstract High throughput approaches are continuously progressing and have become a major part of clinical diagnostics. Still, the critical process of detailed phenotyping and gathering clinical information has not changed much in the last decades. Forms of Next Generation Phenotyping (NGP) are needed to increase further the value of any kind of genetic approaches, including timely considering of (molecular) cytogenetics during the diagnostic quest. As NGP we used in this study the Facial Dysmorphology Novel Analysis (FDNA) technology to automatically identify facial phenotypes associated with Emanuel (ES) and Pall...
Source: Clinical Genetics - June 29, 2017 Category: Genetics & Stem Cells Authors: Liehr T, Acquarola N, Pyle K, St-Pierre S, Rinholm M, Bar O, Wilhelm K, Schreyer I Tags: Clin Genet Source Type: research

A homozygous I684T in GLE1 as a novel cause of arthrogryposis and motor neuron loss.
Abstract Mutations in GLE1, RNA export mediator (GLE1) gene have previously been shown to cause motor neuron diseases such as Lethal congenital contracture syndrome 1 (LCCS1) and Lethal arthrogryposis with anterior horn cell disease (LAAHD), including arthrogryposis, fetal akinesis and motor neuron loss as common clinical features. The homozygous FinMajor mutation p.T144_E145insPFQ has been described as one of the causes for LCCS1 whereas LAAHD is caused by a heterocompound FinMajor mutation together with p.R569H, p.V617M or p.I684T missense mutation. None of these heterocompound missense mutations have previously...
Source: Clinical Genetics - June 28, 2017 Category: Genetics & Stem Cells Authors: Paakkola T, Vuopala K, Kokkonen H, Ignatius J, Valkama M, Moilanen JS, Fahiminiya S, Majewski J, Hinttala R, Uusimaa J Tags: Clin Genet Source Type: research

A 37-years-old Menkes disease patient - Residual ATP7A activity and early copper administration as key factors in beneficial treatment.
h;ller LB Abstract Menkes disease is a lethal disorder characterized by severe neurological symptoms and connective tissue abnormalities; and results from malfunctioning of cuproenzymes, which cannot receive copper due to a defective intracellular copper transporting protein, ATP7A. Early parenteral copper-histidine supplementation may modify disease progression substantially but beneficial effects of long-term treatment have been recorded in only a few patients. Here we report on the eldest surviving Menkes disease patient (37 years) receiving early-onset and long-term copper treatment. He has few neurolog...
Source: Clinical Genetics - June 28, 2017 Category: Genetics & Stem Cells Authors: Tümer Z, Petris M, Zhu S, Mercer J, Bukrinski J, Bilz S, Baerlocher K, Horn N, Møller LB Tags: Clin Genet Source Type: research

A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency.
This report provides evidence that bi-allelic null PAX1 mutations may lead to a multi-system autosomal recessive disorders, where severe combined immunodeficiency might represent the main feature. PMID: 28657137 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - June 28, 2017 Category: Genetics & Stem Cells Authors: Paganini I, Sestini R, Capone GL, Putignano AL, Contini E, Giotti I, Gensini F, Marozza A, Barilaro A, Porfirio B, Papi L Tags: Clin Genet Source Type: research

Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I.
Haack TB Abstract Biallelic mutations in SLC25A46, encoding a modified solute transporter involved in mitochondrial dynamics, have been identified in a wide range of conditions such as hereditary motor and sensory neuropathy with optic atrophy type VIB (OMIM: *610826) and congenital lethal pontocerebellar hypoplasia (PCH). To date, 18 patients from 13 families have been reported, presenting with the key clinical features of optic atrophy, peripheral neuropathy, and cerebellar atrophy. The course of the disease was highly variable ranging from severe muscular hypotonia at birth and early death to first manifestati...
Source: Clinical Genetics - June 27, 2017 Category: Genetics & Stem Cells Authors: Braunisch MC, Gallwitz H, Abicht A, Diebold I, Holinski-Feder E, Van Maldergem L, Lammens M, Kovács-Nagy R, Alhaddad B, Strom TM, Meitinger T, Senderek J, Rudnik-Schöneborn S, Haack TB Tags: Clin Genet Source Type: research

Functional Analysis of p.Ala253_Leu254insAsn Mutation in PLS3 Responsible for X-linked Osteoporosis.
Abstract Mutations in Plastin-3 (PLS3) have been identified as a cause of X-linked osteoporosis. To reveal the molecular mechanism of PLS3 on osteoporosis, we characterized the p.Ala253_Leu254insAsn mutation in PLS3. We first identified Lymphocyte cytosolic protein 1 (LCP1) as a binding partner of PLS3 and the mutation disrupted the interaction between them. We then confirmed the roles of PLS3 and LCP1 in the regulation of intracellular Ca(2+) , which was weakened by the mutant PLS3. Moreover, the interaction between PLS3 and LCP1 was enhanced under a low concentration of extracellular Ca(2+) . However, the mutati...
Source: Clinical Genetics - June 24, 2017 Category: Genetics & Stem Cells Authors: Wang L, Zhai Q, Zhao P, Xiang X, Zhang X, Tian W, Li T Tags: Clin Genet Source Type: research

Spectrum of mutations in cystinuria patients presenting with prenatal hyperechoic colon.
This study shows a relationship between genotype and the clinical form of cystinuria, suggesting that only the patients with the most severe mutations presented with an HEC. These results emphasized the need for prenatal cystinuria screening using classical third-trimester ultrasound scan and the early management of suspected newborns. PMID: 28646536 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - June 24, 2017 Category: Genetics & Stem Cells Authors: Tostivint I, Royer N, Nicolas M, Bourillon A, Czerkiewicz I, Becker PH, Muller F, Benoist JF Tags: Clin Genet Source Type: research

A genetic epidemiology study of Congenital Adrenal Hyperplasia in Italy.
meo G Abstract Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency (21OHD-CAH) is an autosomal recessive disorder affecting steroidogenesis, due to mutations in CYP21A2 (6p21.3). 21OHD-CAH neonatal screening is based on 17-hydroxyprogesterone (17OHP) serum levels, showing high type I error rate and low sensitivity to mild CAH forms. Here, we used an epidemiological approach, which estimates the allelic frequency (q) of an autosomal recessive disorder using the proportion of homozygous patients, the mutational spectrum and the inbreeding coefficient in a sample of affected individuals. We applied this a...
Source: Clinical Genetics - June 23, 2017 Category: Genetics & Stem Cells Authors: Gialluisi A, Menabò S, Baldazzi L, Casula L, Meloni A, Farci MC, Mariotti S, Balestrino L, Ortolano R, Murru S, Carcassi C, Loche S, Balsamo A, Romeo G Tags: Clin Genet Source Type: research

Increasing awareness and knowledge of lifestyle recommendations for cancer prevention in Lynch Syndrome carriers: randomized controlled trial.
In conclusion, provision of WCRF-NL health promotion materials increases awareness and knowledge of lifestyle recommendations for cancer prevention among LS mutation carriers without causing additional distress, but does not affect adherence. PMID: 28632915 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - June 20, 2017 Category: Genetics & Stem Cells Authors: Vrieling A, Visser A, Hoedjes M, Hurks M, Gómez García E, Hoogerbrugge N, Kampman E Tags: Clin Genet Source Type: research

Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis.
In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies. PMID: 28632965 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - June 20, 2017 Category: Genetics & Stem Cells Authors: Papazachariou L, Papagregoriou G, Hadjipanagi D, Demosthenous P, Voskarides K, Koutsofti C, Stylianou K, Ioannou P, Xydakis D, Tzanakis I, Papadaki A, Kallivretakis N, Nikolakakis N, Perysinaki G, Gale DP, Diamantopoulos A, Goudas P, Goumenos D, Soloukide Tags: Clin Genet Source Type: research

Fragile X syndrome: an overview and update of the FMR1 gene.
Abstract Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and the leading form of the monogenic cause of autism. FMR1 premutation is the first single-gene cause of primary ovarian failure (FXPOI) and one of the most common causes of ataxia (FXTAS), multiple additional phenotypes such as fibromyalgia, hypothyroidism, migraine headaches, sleep disturbances, sleep apnea, restless legs syndrome, central pain syndrome, neuropathy and neuropsychiatric alterations has been described. Clinical involvement in men and women carrying the FMR1 premutation currently constitutes a real heal...
Source: Clinical Genetics - June 15, 2017 Category: Genetics & Stem Cells Authors: Mila M, Alvarez-Mora MI, Madrigal I, Rodriguez-Revenga L Tags: Clin Genet Source Type: research

Further delineation of the phenotype caused by biallelic variants in the WDR4 gene.
We report here two sisters harboring compound heterozygous variants of WDR4. Their phenotype differs from that of the first two described patients: they both have a severe microcephaly but only one of the two sisters had a head circumference at birth below -2 SD, their intellectual deficiency is less severe, and they have a GH deficiency and a partial hypogonadotropic hypogonadotropism. One of the two variants is a frameshift mutation, and the other one is a missense occurring in the same nucleotide affected by the first reported pathogenic variant, which could therefore be a mutational hot spot. The description of these t...
Source: Clinical Genetics - June 15, 2017 Category: Genetics & Stem Cells Authors: Trimouille A, Lasseaux E, Barat P, Deiller C, Drunat S, Rooryck C, Arveiler B, Lacombe D Tags: Clin Genet Source Type: research

Genetic epidemiology of Familial Mediterranean Fever through integrative analysis of whole genome and exome sequences from Middle East and North Africa.
Abstract Familial Mediterranean fever (FMF), an autosomal recessive and rare autoinflammatory disease is caused by genetic mutations in the MEFV gene and is highly prevalent in the Mediterranean basin. Though the carrier frequency of specific disease variants in the MEFV gene has been reported from isolated studies, a comprehensive view of variants in the Mediterranean region has not been possible due to paucity of data. The recent availability of whole-genome and whole-exome datasets prompted us to study the genetic epidemiology of MEFV variants in the region. We assembled data from five datasets encompassing who...
Source: Clinical Genetics - June 9, 2017 Category: Genetics & Stem Cells Authors: Koshy R, Sivadas A, Scaria V Tags: Clin Genet Source Type: research

Large-scale Study of Clinical and Biochemical Characteristics of Chinese Patients Diagnosed with Krabbe Disease.
This study investigated 22 unrelated Chinese patients, including their clinical presentations, plasma psychosine levels and GALC gene mutations. We found the late-onset form of KD present in 82% of the patients in our study, which was more prevalent than in patients from other populations. Plasma psychosine levels were elevated in KD, which were correlated with the severity of clinical presentations. Sanger sequencing identified 8 novel mutations, including 7 missense mutations, p.H253Y, p.S259L, p.P318L, p.F350V, p.T428A, p.L530P, p.G586D, and 1 splicing mutation, c.1251+1G>A. Quantitative real-time PCR and multiplex l...
Source: Clinical Genetics - June 9, 2017 Category: Genetics & Stem Cells Authors: Zhao S, Zhan X, Wang Y, Ye J, Han L, Qiu W, Gao X, Gu X, Zhang H Tags: Clin Genet Source Type: research

Genetic Study of Early-onset Graves' Disease in the Chinese Han Population.
Abstract Graves' disease (GD) is a complex autoimmune disorder in which genetic and environmental factors are both involved in the pathogenesis. Early-onset patients have a shorter exposure time to environmental factors and are, therefore, good models to help understand the genetic architecture of GD. Based on previous studies of early-onset GD, eleven single nucleotide polymorphisms (SNPs) and their related SNPs (R(2)> 0.6), SNPs located within a ± 1-Mb region of the FOXP3 gene, and twenty validated GD-risk SNPs were selected and screened for genotyping in 3,735 GD and 4,893 control patien...
Source: Clinical Genetics - June 9, 2017 Category: Genetics & Stem Cells Authors: Yuan FF, Ye XP, Liu W, Xue LQ, Ma YR, Zhang LL, Zhang MM, Sun F, Wan YY, Zhang QY, Zhao SX, Song HD, China Consortium for the Genetics of Autoimmune Thyroid Disease Tags: Clin Genet Source Type: research

Novel biallelic mutations in the PNPT1 gene encoding a mitochondrial-RNA-import protein PNPase cause delayed myelination.
We report here two siblings with PNPT1 mutations who presented delayed myelination as well as mitochondrial dysfunction. We identified compound heterozygous mutations (c.227G>A; p.Gly76Asp and c.574C>T; p.Arg192*) in PNPT1 by quartet whole-exome sequencing. Analyses of skin fibroblasts from the patient showed that PNPase expression was markedly decreased and that import of the small RNA RNase P into mitochondria was impaired. Exogenous expression of wild-type PNPT1, but not mutants, rescued ATP production in patient skin fibroblasts, suggesting the pathogenicity of the identified mutations. Our cases expand the pheno...
Source: Clinical Genetics - June 8, 2017 Category: Genetics & Stem Cells Authors: Sato R, Arai-Ichinoi N, Kikuchi A, Matsuhashi T, Numata-Uematsu Y, Uematsu M, Fujii Y, Murayama K, Ohtake A, Abe T, Kure S Tags: Clin Genet Source Type: research

Distinguishing pathogenic mutations from background genetic noise in cardiology: the use of large genome databases for genetic interpretation.
Abstract Advances in clinical genetic testing has led to increased insight into the human genome, including how challenging it is to interpret rare genetic variation. In some cases, the ability to detect genetic mutations exceeds the ability to understand their clinical impact, limiting the advantage of these technologies. Obstacles in genomic medicine are many and include: understanding the level of certainty/uncertainty behind pathogenicity determination, the numerous different variant interpretation-guidelines used by clinical laboratories, delivering the certain or uncertain result to the patient, helping pati...
Source: Clinical Genetics - June 6, 2017 Category: Genetics & Stem Cells Authors: Ghouse J, Skov MW, Bigseth RS, Ahlberg G, Kanters JK, Olesen MS Tags: Clin Genet Source Type: research

Identification of novel BCL11A variants in patients with epileptic encephalopathy: expanding the phenotypic spectrum.
In this study, we performed whole-exome sequencing of 302 patients with epileptic encephalopathies (EEs), and identified two novel BCL11A variants, c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr). Both patients shared major physical features characteristic of BCL11A-related intellectual disability syndrome, suggesting that characteristic physical features and the persistence of HbF should lead clinicians to suspect EEs caused by BCL11A pathogenic variants. Patient 1, with a frameshift variant, presented with Lennox-Gastaut syndrome, which expands the phenotypic spectrum of BCL11A haploinsufficiency. Patient 2, w...
Source: Clinical Genetics - June 6, 2017 Category: Genetics & Stem Cells Authors: Yoshida M, Nakashima M, Okanishi T, Kanai S, Fujimoto A, Itomi K, Morimoto M, Saitsu H, Kato M, Matsumoto N, Chiyonobu T Tags: Clin Genet Source Type: research

Performance of BRCA1/2 mutation prediction models in male breast cancer patients.
Asperen CJ Abstract To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA, BRCAPRO and the Myriad prevalence table ('Myriad'). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed versus predicted carriers and assessed the area under the receiver operating characteristic (ROC) curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 m...
Source: Clinical Genetics - June 6, 2017 Category: Genetics & Stem Cells Authors: Moghadasi S, Grundeken V, Janssen LAM, Dijkstra NH, Rodríguez-Girondo M, van Zelst-Stams WAG, Oosterwijk JC, Ausems MGEM, Oldenburg RA, Adank MA, Blom EW, Ruijs M, van Os TAM, van Deurzen CHM, Martens JWM, Schroder CP, Wijnen JT, Vreeswijk MPG, van Asper Tags: Clin Genet Source Type: research

Mutation Screening of 10 Cancer Susceptibility Genes in Unselected Breast Cancer Patients.
This study was performed to investigate the spectrum and prevalence of mutations in 10 cancer susceptibility genes in paired tumor/normal tissues of 292 unselected Chinese breast cancer patients. We performed an analysis of germline and somatic variants in ATM, CDH1, CHEK2, ESR1, GATA3, MAP3K1, MSH2, PALB2, RB1 and STK11 genes by integrating microfluidic PCR-based target enrichment and next-generation sequencing technologies. In total, 3 germline and 25 somatic deleterious mutations were found among 27 patients (9.25%), and 17 of them were novel mutations. Most deleterious mutations were prevalent in luminal A invasive bre...
Source: Clinical Genetics - June 5, 2017 Category: Genetics & Stem Cells Authors: Xie Y, Guoli L, Chen M, Guo X, Tang L, Luo X, Wang S, Yi W, Dai L, Wang J Tags: Clin Genet Source Type: research

Diagnostic application of a capture based NGS test for the concurrent detection of variants in sequence and copy number as well as LOH.
Abstract Whole exome sequencing has made increasingly accessible the identification of causative SNVs/InDels associated with rare Mendelian conditions. Incorporation of softwares allowing CNVs detection into the WES bioinformatics pipelines may increase the diagnostic yield. However, no standard protocols for this analysis are so far available and CNVs in non-coding regions are totally missed by WES, in spite of their possible role in the regulation of the flanking genes expression. So, in a number of cases the diagnostic workflow contemplates an initial investigation by genomic arrays followed, in the negative ca...
Source: Clinical Genetics - May 30, 2017 Category: Genetics & Stem Cells Authors: Vetro A, Godin D, Lesende I, Limongelli I, Ranzani GN, Novara F, Bonaglia MC, Rinaldi B, Franchi F, Manolakos E, Lonardo F, Scarano F, Scarano G, Costantino L, Tedeschi S, Giglio S, Zuffardi O Tags: Clin Genet Source Type: research

Novel biallelic SZT2 mutations in three cases of early-onset epileptic encephalopathy.
In this study, we identified by whole-exome sequencing compound heterozygous SZT2 mutations in three patients with early-onset epileptic encephalopathies. Six novel SZT2 mutations were found, including three truncating, one splice site and two missense mutations. The splice site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealing a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of two cases. Interest...
Source: Clinical Genetics - May 30, 2017 Category: Genetics & Stem Cells Authors: Tshuchida N, Nakashima M, Miyauchi A, Yoshitomi S, Kimizu T, Ganesan V, Wee Teik K, Gaik-Siew C, Kato M, Mizuguchi T, Takata A, Miyatake S, Miyake N, Osaka H, Yamagata T, Hideaki N, Saitsu H, Matsumoto N Tags: Clin Genet Source Type: research

A familial study of twins with severe asthenozoospermia identified a homozygous SPAG17 mutation by whole-exome sequencing.
Abstract Asthenozoospermia (AZS) is a common cause of male infertility, characterized by abnormal reduction in the motility of ejaculated spermatozoa. Here, in a patient from a consanguineous family, we identified a homozygous mutation (c.G4343A, p.R1448Q) in SPAG17 by whole-exome sequencing. The encoded protein, SPAG17, localizes to the axonemal central apparatus and is considered essential for flagellar waveform. In silico analysis revealed that R1448Q is a potential pathogenic mutation. Immunostaining and western blot assays showed that the R1448Q mutation may exert a negative effect on the steady-state of the ...
Source: Clinical Genetics - May 26, 2017 Category: Genetics & Stem Cells Authors: Xu X, Sha YW, Mei LB, Ji ZY, Qiu PP, Ji H, Li P, Wang T, Li L Tags: Clin Genet Source Type: research

Novel COL4A2 variant in a large pedigree: Consequences and dilemmas.
Abstract Pathogenic COL4A2 variants cause abnormalities in collagen production and can have serious implications for a range of organ systems, most notably the brain. Herein, we describe a large family of first-degree relatives affected by a novel heterozygous variant in COL4A2 (c.3490G.A). A wide disease spectrum is described, from asymptomatic to symptomatic, including 2 children with porencephaly and co-existing juvenile idiopathic polyarthritis. During a subsequent pregnancy, antenatal testing identified a positive fetus. In view of the literature, we review management and genetic counselling dilemmas. PM...
Source: Clinical Genetics - May 25, 2017 Category: Genetics & Stem Cells Authors: McGovern M, Flanagan O, Lynch B, Lynch SA, Allen NM Tags: Clin Genet Source Type: research

On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation.
Espinós C Abstract Neurodegeneration with brain iron accumulation (NBIA) are a group of inherited heterogeneous neurodegenerative rare disorders. These patients present with dystonia, spasticity, parkinsonism and neuropsychiatric disturbances, along with brain MRI evidence of iron accumulation. In sum, they are devastating disorders and to date, there is no specific treatment. Ten NBIA genes are accepted: PANK2, PLA2G6, C19orf12, COASY, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17, and. Nonetheless, a relevant percentage of patients remain without genetic diagnosis, suggesting that other novel NBIA genes rema...
Source: Clinical Genetics - May 23, 2017 Category: Genetics & Stem Cells Authors: Tello C, Darling A, Lupo V, Pérez-Dueñas B, Espinós C Tags: Clin Genet Source Type: research

Disruption of YWHAE gene at 17p13.3 causes learning disabilities and brain abnormalities.
Abstract There is a broad phenotypic spectrum of patients with 17p13.3 deletions. One of the most prominent features is lissencephaly caused by haploinsufficiency of the gene PAFAH1B1. The deletion of this gene and those distal to it, results in Miller-Dieker syndrome, however there have been many reports of patients with haploinsufficiency of the distal genes alone. The deletions of these genes including YWHAE, CRK and TUSC5 have been studied extensively and YWHAE has been postulated to be the cause of neurological abnormalities. The patients with deletions of the Miller-Dieker syndrome distal region present with...
Source: Clinical Genetics - May 23, 2017 Category: Genetics & Stem Cells Authors: Noor A, Bogatan S, Watkins N, Meschino WS, Stavropoulos DJ Tags: Clin Genet Source Type: research

Clinical, Biochemical, and Genetic Aspects of Sj ögren-Larsson Syndrome.
Clinical, Biochemical, and Genetic Aspects of Sjögren-Larsson Syndrome. Clin Genet. 2017 May 23;: Authors: Cho KH, Shim SH, Kim M Abstract Sjögren-Larsson syndrome (SLS) is caused by an autosomal recessive mutation in ALDH3A2, which encodes the fatty aldehyde dehydrogenase responsible for the metabolism of long-chain aliphatic aldehydes and alcohols. The pathophysiologic accumulation of aldehydes in various organs, including the skin, brain, and eyes, leads to characteristic features of ichthyosis, intellectual disability, spastic di-/quadriplegia, and low visual acuity with photophobia. The...
Source: Clinical Genetics - May 23, 2017 Category: Genetics & Stem Cells Authors: Cho KH, Shim SH, Kim M Tags: Clin Genet Source Type: research

A Homozygous Potentially Pathogenic Variant in the PAXBP1 Gene in a Large Family with Global Developmental Delay and Myopathic Hypotonia.
Abstract PAX binding protein 1 (PAXBP1) is an adaptor protein linking the transcription factor PAX3 and PAX7 to the histone methylation machinery. PAXBP1 is a nuclear protein and its high expression is known in brain cerebellar hemisphere and cerebellum. Moreover, it is also found in abundance in muscle precursor cells that are involved in myogenesis and skeletal muscles formation. Whole genome SNP genotyping and exome sequencing in a family with distinct syndrome of global developmental delay and hypotonia mapped the disease locus to the chromosome 21q22.11 and identified a homozygous missense variant (c.1612C>...
Source: Clinical Genetics - May 19, 2017 Category: Genetics & Stem Cells Authors: Alharby E, Albalawi AM, Nasir A, Alhijji SA, Mahmood A, Ramzan K, Abdusamad F, Aljohani A, Abdelsalam O, Eldardear A, Basit S Tags: Clin Genet Source Type: research

WDR45B-related intellectual disability, spastic quadriplegia, epilepsy, and cerebral hypoplasia: a consistent neurodevelopmental syndrome.
In this report we present six individuals from three unrelated families with homozygous pathogenic variants in WDR45B: c.799C>T (p.Q267*) in one family and c.673C>T (p.R225*) in two families. These individuals shared a similar phenotype including profound development delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations. Neuroimaging showed ventriculomegaly, reduced cerebral white matter volume, and thinning of cerebral gray matter. The consistency in the phenotype strongly supports that WDR45B is associated with this disease. PMID: 28503735 [PubMed - ...
Source: Clinical Genetics - May 14, 2017 Category: Genetics & Stem Cells Authors: Suleiman J, Allingham-Hawkins D, Hashem M, Shamseddin H, Alkuraya FS, El-Hattab AW Tags: Clin Genet Source Type: research

The Penetrance of Paraganglioma and Pheochromocytoma in SDHB germline mutation carriers.
en EF Abstract Germline mutations in SDHB predispose to hereditary paraganglioma syndrome type 4. The risk of developing paraganglioma (PGL) or pheochromocytoma (PHEO) in SDHB mutation carriers is subject of recent debate. In the present nationwide cohort study of SDHB mutation carriers identified by the clinical genetics centers of the Netherlands, we have calculated the penetrance of SDHB associated tumors using a novel maximum likelihood estimator. This estimator addresses ascertainment bias and missing data on pedigree size and structure. 195 SDHB mutation carriers were included, carrying 27 different SDHB mut...
Source: Clinical Genetics - May 14, 2017 Category: Genetics & Stem Cells Authors: Rijken JA, Niemeijer ND, Jonker MA, Eijkelenkamp K, Jansen JC, van Berkel A, M Timmers HJL, Kunst HPM, Bisschop PHLT, Kerstens MN, Dreijerink KMA, van Dooren MF, van der Horst-Schrivers ANA, Hes FJ, René Leemans C, Corssmit EPM, Hensen EF Tags: Clin Genet Source Type: research

Constitutional mismatch repair deficiency in a healthy child: on the spot diagnosis?
We report of a case of a healthy six-year-old girl who fulfilled the diagnostic criteria of NF1 with>6 CALM and freckling. Since molecular genetic testing was unable to confirm the diagnosis of NF1 or Legius syndrome and the patient was a child of consanguineous parents, we suspected CMMRD and found a homozygous PMS2 mutation that impairs MMR function. Current guidelines advise testing for CMMRD only in cancer patients. However, this case illustrates that including CMMRD in the differential diagnosis in suspected sporadic NF1 without causative NF1 or SPRED1 mutations may facilitate identification of CMMRD prior to cance...
Source: Clinical Genetics - May 14, 2017 Category: Genetics & Stem Cells Authors: Suerink M, Potjer TP, Versluijs AB, Ten Broeke SW, Tops CM, Wimmer K, Nielsen M Tags: Clin Genet Source Type: research

Spectrum of mucocutaneous, ocular and facial features and delineation of novel presentations in 62 classical Ehlers-Danlos syndrome patients.
Abstract Classical Ehlers-Danlos syndrome (cEDS) is characterized by marked cutaneous involvement that is defined by many criteria of the Villefranche nosology and the 2017 revision. However, the diagnostic flow-chart that prompts molecular testing is still based on experts' opinion rather than systematic published data. Here we report on 62 molecularly characterized cEDS patients with focus on skin, mucosae, face, and joint hypermobility. The major and minor Villefranche criteria, additional 11 mucocutaneous signs and 15 facial dysmorphic traits were ascertained and feature rates compared by sex and age. In our c...
Source: Clinical Genetics - May 9, 2017 Category: Genetics & Stem Cells Authors: Colombi M, Dordoni C, Venturini M, Ciaccio C, Morlino S, Chiarelli N, Zanca A, Calzavara-Pinton P, Zoppi N, Castori M, Ritelli M Tags: Clin Genet Source Type: research

MMP family polymorphisms and the risk of aortic aneurysmal disease: A systematic review and meta-analysis.
In this study, we conducted a systematic review with an update meta-analysis to investigate the relationship between MMP family polymorphisms and aortic aneurysmal diseases. We systematically reviewed 24 polymorphisms in eight MMP genes related to the risk of abdominal aortic aneurysm (AAA), thoracic aortic aneurysm (TAA) or thoracic aortic dissection (TAD). A total of 19 case-control studies with 15 highly studied MMP polymorphisms were included in our meta-analysis. Our results suggested that MMP2rs243865, MMP3rs3025058, MMP13rs2252070 polymorphisms were significantly associated with AAA risk, MMP2rs11643630, MMP8rs11225...
Source: Clinical Genetics - May 9, 2017 Category: Genetics & Stem Cells Authors: Li T, Lv Z, Jing JJ, Yang J, Yuan Y Tags: Clin Genet Source Type: research

A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures.
Abstract Epilepsy of infancy with migrating focal seizures (EIMFS) is an infantile epileptic encephalopathy characterized by refractory seizures, severe psychomotor delay, and multiple moving epileptic discharges. The genetic etiology of EIMFS is relatively homogeneous with the majority of causative mutations found in KCNT1. Currently, gene panel or whole-exome sequencing is used for testing. To verify the pathogenicity of a variant, co-segregation of the variant and the disorder in a pedigree is important; hence, de novo mutations that are judged to be deleterious may be considered pathogenic because the patients...
Source: Clinical Genetics - May 6, 2017 Category: Genetics & Stem Cells Authors: Saito T, Ishii A, Sugai K, Sasaki M, Hirose S Tags: Clin Genet Source Type: research

ARL6IP1 mutation causes congenital insensivity to pain, self-mutilation and spastic paraplegia.
This report highlights the role of ARL6IP1 in the pathophysiology of insensitivity to pain and spastic paraplegia. PMID: 28471035 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - May 4, 2017 Category: Genetics & Stem Cells Authors: Nizon M, Küry S, Péréon Y, Besnard T, Quinquis D, Boisseau P, Marsaud T, Magot A, Mussini JM, Mayrargue E, Barbarot S, Bézieau S, Isidor B Tags: Clin Genet Source Type: research

New mutations in GJA8 expand the phenotype to include total sclerocornea.
Abstract This project expands the disease spectrum for mutations in GJA8 to include total sclerocornea, rudimentary lenses and microphthalmia, in addition to this gene's previously known role in isolated congenital cataracts. Ophthalmic findings revealed bilateral total sclerocornea in three probands, with small abnormal lenses in two of the cases, and cataracts and microphthalmia in one case. Next-generation sequencing revealed de novo heterozygous mutations affecting the same codon of GJA8: (c.281G>A; p.(Gly94Glu) and c.280G>C; p.(Gly94Arg)) in two of the probands, in addition to the c.151G>A; p.(Asp51A...
Source: Clinical Genetics - April 29, 2017 Category: Genetics & Stem Cells Authors: Ma AS, Grigg JR, Prokudin I, Flaherty M, Bennetts B, Jamieson RV Tags: Clin Genet Source Type: research

Multiple spinal nerve enlargement and SOS1 mutation: further evidence of overlap between Neurofibromatosis type 1 and Noonan phenotype.
We describe a 15-year-old boy, whose mother previously received clinical diagnosis of NF1 due to presence of bilateral cervical and lumbar spinal lesions resembling plexiform neurofibromas and features suggestive of Noonan syndrome. NF1 molecular analysis was negative in the mother. The boy presented with Noonan features, multiple lentigines and pectus excavatum. NGS analysis of all RASopathy genes identified p.Ser548Arg missense mutation in SOS1 in the boy, confirmed in his mother. Brain and spinal MRI scans were negative in the boy. No heart involvement or deafness was observed in proband or mother. This is the first rep...
Source: Clinical Genetics - April 29, 2017 Category: Genetics & Stem Cells Authors: Santoro C, Giugliano T, Melone MAB, Cirillo M, Schettino C, Bernardo P, Cirillo G, Perrotta S, Piluso G Tags: Clin Genet Source Type: research

The association of severe encephalopathy and question mark ear is highly suggestive of loss of MEF2C function.
We report heterozygous MEF2C loss-of-function as a possible cause of question mark ear associated with intellectual deficiency. PMID: 28456137 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - April 29, 2017 Category: Genetics & Stem Cells Authors: Gordon CT, Tessier A, Demir Z, Goldenberg A, Oufadem M, Voisin N, Pingault V, Bienvenu T, Lyonnet S, de Pontual L, Amiel J Tags: Clin Genet Source Type: research

A novel TRPA1 variant is associated with carbamazepine-responsive cramp-fasciculation syndrome.
uiz C Abstract Cramp-fasciculation syndrome (CFS) is a rare muscle hyperexcitability syndrome that presents with muscle cramps, fasciculations, and stiffness, as well as pain, fatigue, anxiety, hyperreflexia, and paresthesias. Although familial cases have been reported, a genetic etiology has not yet been identified. We performed whole-exome sequencing followed by validation and cosegregation analyses on a father-son pair with CFS. Both subjects manifested other hypersensitivity-hyperexcitability symptoms, including asthma, gastroesophageal reflux, migraine, restless legs syndrome, tremor, cold hyperalgesia, and c...
Source: Clinical Genetics - April 24, 2017 Category: Genetics & Stem Cells Authors: Nirenberg MJ, Chaouni R, Biller TM, Gilbert RM, Paisán-Ruiz C Tags: Clin Genet Source Type: research