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Variants in CIB2 cause DFNB48 and not USH1J.
This report is the first to show that biallelic loss of function variants in CIB2 cause ARNSHL and not USH. In the era of precision medicine, providing the correct diagnosis (NSHL vs USH) is essential for patient care as it impacts potential intervention and prevention options for patients. Here we provide evidence disqualifying CIB2 as an USH-causing gene. PMID: 29112224 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - November 7, 2017 Category: Genetics & Stem Cells Authors: Booth KT, Kahrizi K, Babanejad M, Daghagh H, Bademci G, Arzhangi S, Zareabdollahi D, Duman D, El-Amraoui A, Tekin M, Najmabadi H, Azaiez H, Smith RJ Tags: Clin Genet Source Type: research

Richieri-Costa-Pereira syndrome: expanding its phenotypic and genotypic spectrum.
This study has expanded the phenotype in this syndrome by the observation of microcephaly, better characterization of skeletal abnormalities, less severe phenotype with only mild facial dysmorphisms and limb anomalies, as well as the absence of cleft mandible, which is a hallmark of the syndrome. Although the most frequent mutation in this study was the recurrent 16-repeat expansion in EIF4A3, there was an overrepresentation of the 14-repeat expansion, with mild phenotypic expression, thus suggesting that the number of these motifs could play a role in phenotypic delineation. PMID: 29112243 [PubMed - as supplied by pu...
Source: Clinical Genetics - November 7, 2017 Category: Genetics & Stem Cells Authors: Bertola DR, Hsia G, Alvizi L, Gardham A, Wakeling E, Yamamoto GL, Honjo RS, Oliveira LAN, Di Francesco RC, Perez BA, Kim CA, Passos-Bueno MR Tags: Clin Genet Source Type: research

Epidemiology of Huntington Disease in Cyprus: A 20-Year Retrospective Study.
Abstract Huntington disease (HD) is most prevalent among populations of western European descent and isolated populations where founder effects may operate. The aim of this study was to examine the epidemiology of HD in Cyprus, an island in southern Europe with extensive western European colonization in the past. All registered HD patients in the Cyprus Republic, since 1994, were included. Detailed pedigrees and clinical information were recorded and maps, showing the geographic distribution of HD, were constructed. Requests for genetic testing were also examined. The project identified 58 clinically manifested ca...
Source: Clinical Genetics - November 6, 2017 Category: Genetics & Stem Cells Authors: Demetriou CA, Heraclides A, Salafori C, Tanteles GA, Christodoulou K, Christou Y, Zamba-Papanicolaou E Tags: Clin Genet Source Type: research

Conversations with French Medical Geneticists. A Personal Perspective on the Origins and Early Years of Medical Genetics in France.
Abstract The history of the beginnings of medical genetics in France is discussed, based on the personal perspective provided by recorded interviews with 16 early French workers in the field. The weakness of French genetics overall up to the beginning of the Second World War meant that post-war medical genetics had to start from new, with its origins largely derived from the medical fields of child health and the prevention of genetic disorders, rather than from basic science. The key people responsible for initiating these developments were Robert Debré and Maurice Lamy at Hôpital Necker in Paris and...
Source: Clinical Genetics - November 3, 2017 Category: Genetics & Stem Cells Authors: Harper PS Tags: Clin Genet Source Type: research

Biallelic mutations in FLNB cause a skeletal dysplasia with 46,XY gonadal dysgenesis by activating β-catenin.
Biallelic mutations in FLNB cause a skeletal dysplasia with 46,XY gonadal dysgenesis by activating β-catenin. Clin Genet. 2017 Nov 02;: Authors: Upadhyay K, Loke J, O V, Taragin B, Ostrer H Abstract Filamin B (FLNB) functions as a switch that can affect chrondrocyte development and endochondral bone formation through a series of signaling molecules and transcription factors that also affect Sertoli cell development. Here, we report a subject with a novel skeletal dysplasia and co-existing 46,XY gonadal dysgenesis and biallelic mutations in FLNB. Whole exome sequencing was performed to identify mu...
Source: Clinical Genetics - November 2, 2017 Category: Genetics & Stem Cells Authors: Upadhyay K, Loke J, O V, Taragin B, Ostrer H Tags: Clin Genet Source Type: research

Homozygous Mutation in ELMO2 may cause Ramon syndrome.
We report on a girl, born to first cousin Lebanese parents, with intellectual disability, seizures, repeated gingivorrhagia, enlarged lower and upper jaws, overgrowth of the gums, high arched and narrow palate, crowded teeth, hirsutism of the back, large abdomen and a small umbilical hernia. Cysts of the mandible, fibrous dysplasia of bones, and enlarged adenoids causing around 60% narrowing of the nasopharyngeal airways were noted at radiographic examination. Her brother presented with the same features in addition to a short stature, an ostium secundum, and more pronounced intellectual disability. He died at the age of 8...
Source: Clinical Genetics - November 2, 2017 Category: Genetics & Stem Cells Authors: Mehawej C, Hoischen A, Farah RA, Marey I, David M, Stora S, Lachlan K, Brunner HG, Mégarbané A Tags: Clin Genet Source Type: research

Response to Ciuculete et al.
PMID: 28990170 [PubMed - in process] (Source: Clinical Genetics)
Source: Clinical Genetics - October 12, 2017 Category: Genetics & Stem Cells Authors: Smit RAJ, le Cessie S, Jukema JW, Trompet S Tags: Clin Genet Source Type: research

Response to Lefebvre et al.
Abstract Congenital scoliosis (CS) is a common vertebral malformation with incidence of up to 1 of 1000 births worldwide. Recently, TBX6 has been reported as the first disease gene for CS: about 10% of CS patients are compound heterozygotes of rare null mutations and a common haplotype composed by 3 SNPs in TBX6. Lefebvre et al in this journal reported that 2 patients with spondylocostal dysostosis (SCD), a rare skeletal dysplasia affecting spine and ribs also have TBX6 mutations: 1 carried the microdeletion and a rare missense variant, and another 2 rare missense variants. We investigated the pathogenicity of the...
Source: Clinical Genetics - October 12, 2017 Category: Genetics & Stem Cells Authors: Takeda K, Kou I, Kawakami N, Yasuhiko Y, Ogura Y, Imagawa E, Miyake N, Matsumoto N, Sudo H, Kotani T, Japan Early Onset Scoliosis Research Group, Nakamura M, Matsumoto M, Watanabe K, Ikegawa S Tags: Clin Genet Source Type: research

Response to Leusink et al.
i J PMID: 28990172 [PubMed - in process] (Source: Clinical Genetics)
Source: Clinical Genetics - October 12, 2017 Category: Genetics & Stem Cells Authors: Ciuculete DM, Schiöth HB, Mwinyi J Tags: Clin Genet Source Type: research

Prader-Willi Syndrome Genetic Subtypes and Clinical Neuropsychiatric Diagnoses in Residential Care Adults.
Abstract The historical diagnosis of Prader-Willi syndrome (PWS), a complex genetic disorder, in adults by clinical presentation rather than genetic testing has limited genetic subtype-specific psychometric investigations and treatment. Genetic testing and clinical psychiatric evaluation using DSM-IV-TR criteria were undertaken on 72 adult residents (34M; 38F) from the Prader-Willi Homes of Oconomowoc (PWHO), a specialty PWS group home system. Methylation specific-multiplex ligation probe amplification and high-resolution microarrays were analyzed for methylation status, 15q11-q13 deletions and maternal uniparenta...
Source: Clinical Genetics - October 6, 2017 Category: Genetics & Stem Cells Authors: Manzardo AM, Weisensel N, Ayala S, Hossain W, Butler MG Tags: Clin Genet Source Type: research

A novel missense mutation affecting the same amino acid as the recurrent PACS1 mutation in Schuurs-Hoeijmakers syndrome.
Abstract A novel causative variant (c.608G>A, p.Arg203Gln) in PACS1. PMID: 28975623 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - October 4, 2017 Category: Genetics & Stem Cells Authors: Miyake N, Ozasa S, Mabe H, Kimura S, Shiina M, Imagawa E, Miyatake S, Nakashima M, Mizuguchi T, Takata A, Ogata K, Matsumoto N Tags: Clin Genet Source Type: research

WNT10A gene is the second molecular candidate in a cohort of young Italian subjects with ectodermal derivative impairment (EDI).
This study is the first to show that, after ED1, WNT10A is the second molecular candidate for EDI in a large Italian Caucasian population. The study confirmed that Phe228Ile is the most frequent WNT10A variant in Caucasian populations, and that WNT10A mutations are associated with large variability in EDI. PMID: 28976000 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - October 4, 2017 Category: Genetics & Stem Cells Authors: Guazzarotti L, Tadini G, Mancini GE, Sani I, Pisanelli S, Galderisi F, D'Auria E, Secondi R, Bottero A, Zuccotti GV Tags: Clin Genet Source Type: research

Digenic inheritance and genetic modifiers.
Abstract Digenic inheritance (DI) concerns pathologies with the simplest form of multigenic aetiology, implicating more than one gene (and perhaps the environment). True DI is when biallelic or even triallelic mutations in two distinct genes, in cis or in trans, are necessary and sufficient to cause pathology with a defined diagnosis. In true DI, a heterozygous mutation in each of two genes alone is not associated with a recognizable phenotype. Well-documented diseases with true DI are so far rare and follow non-Mendelian inheritance. DI is also encountered when by serendipity, pathogenic mutations responsible for...
Source: Clinical Genetics - October 4, 2017 Category: Genetics & Stem Cells Authors: Deltas C Tags: Clin Genet Source Type: research

MLEC gene polymorphisms promote cerebral palsy via M2-like macrophage polarization.
Abstract The relationship between gene polymorphisms and the pathogenesis of cerebral palsy (CP) is uncovering recently. Here, we suggested that single nucleotide polymorphisms (SNPs) of MLEC gene might take part in the pathogenesis of CP. We genotyped and analyzed six SNP positions of MLEC gene in 916 CP patients and 957 healthy people, which are from the Chinese Han population. The results indicated significant associations between the risk of CP and rs10431386 (allele: p-value = 0.006, odds ratio (OR) = 1.587, 95% confidence interval (CI) = 1.198-1.967) and rs7964786 (a...
Source: Clinical Genetics - October 3, 2017 Category: Genetics & Stem Cells Authors: Shi W, Zhu Y, Zhou M, Ruan Y, Chen X, Chen X Tags: Clin Genet Source Type: research

Axenfeld-Rieger syndrome.
Abstract Axenfeld-Rieger syndrome (ARS) is a clinically and genetically heterogeneous group of developmental disorders affecting primarily the anterior segment of the eye, often leading to secondary glaucoma. Patients with ARS may also present with systemic changes including dental defects, mild craniofacial dysmorphism, and umbilical anomalies. ARS is inherited in an autosomal dominant fashion; the underlying defect in 40% of patients is mutations in PITX2 or FOXC1. Here, an overview of the clinical spectrum of ARS is provided. As well, the known underlying genetic defects, clinical diagnostic possibilities, gene...
Source: Clinical Genetics - October 3, 2017 Category: Genetics & Stem Cells Authors: Seifi M, Walter MA Tags: Clin Genet Source Type: research

Autism spectrum disorder recurrence, resulting of germline mosaicism for a CHD2 gene missense variant.
Abstract Germline mosaicism for a novel missense variant p.Thr645Met located in the SNF2-related ATP dependent helicase domain of CHD2 in 2 affected siblings with autism spectrum disorder. PMID: 28960266 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - September 28, 2017 Category: Genetics & Stem Cells Authors: Lebrun N, Parent P, Gendras J, Billuart P, Poirier K, Bienvenu T Tags: Clin Genet Source Type: research

Genomic disorders 20 years on - mechanisms for clinical manifestations.
Abstract Genomic disorders result from copy number variants (CNVs) or submicroscopic rearrangements of the genome rather than from single nucleotide variants (SNVs). Diverse technologies, including array comparative genomic hybridization (aCGH) and, more recently, whole genome sequencing and whole exome sequencing, have enabled robust genome-wide unbiased detection of CNVs in affected individuals and in reportedly healthy controls. Sequencing of breakpoint junctions has allowed for elucidation of upstream mechanisms leading to genomic instability and resultant structural variation, whereas studies of the associati...
Source: Clinical Genetics - September 26, 2017 Category: Genetics & Stem Cells Authors: Harel T, Lupski JR Tags: Clin Genet Source Type: research

Hypoglycaemia Represents a Clinically Significant Manifestation of PIK3CA- and CCND2-Associated Segmental Overgrowth.
We report a cohort of 6 children with megalencephaly-capillary malformation syndrome (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus syndrome (MPPH) who developed clinically significant hypoglycaemia. Based on our findings, we suggest that segmental overgrowth patients should be screened for low blood glucose levels during childhood and there should be early specialist endocrine review in any children who develop hypoglycaemia. PMID: 28941273 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - September 23, 2017 Category: Genetics & Stem Cells Authors: Jh MD, Hickson N, Banerjee I, Murray PG, Ram D, Metcalfe K, Clayton-Smith J, Douzgou S Tags: Clin Genet Source Type: research

INPP5K variant causes autosomal recessive congenital cataract in a Pakistani family.
Abstract Congenital cataract (CC) is clinically and genetically highly heterogeneous. Here, we enrolled a consanguineous kindred (LUCC15) from Pakistan, with three affected individuals suffering with CC. Exome sequencing revealed a transition mutation [c.149T>C; p.(Ile50Thr)] in INPP5K. Inositol polyphosphate-5-phosphatase K, encoded by INPP5K, is involved in dephosphorylation of phosphatidylinositol (PtdIns) 4,5-bisphosphate, and PtdIns 3,4,5-trisphosphate. Recently, pathogenic variants in INPP5K have been reported in families with congenital muscular dystrophies, intellectual disability, and cataract. In our ...
Source: Clinical Genetics - September 22, 2017 Category: Genetics & Stem Cells Authors: Yousaf S, Sheikh SA, Riazuddin S, Waryah AM, Ahmed ZM Tags: Clin Genet Source Type: research

Detection of copy number variations in epilepsy using exome data.
Goldberg-Stern H, Uchiyama Y, Imagawa E, Mizuguchi T, Takata A, Miyake N, Nakajima H, Saitsu H, Miyatake S, Matsumoto N Abstract Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide varia...
Source: Clinical Genetics - September 22, 2017 Category: Genetics & Stem Cells Authors: Tsuchida N, Nakashima M, Kato M, Heyman E, Inui T, Haginoya K, Watanabe S, Chiyonobu T, Morimoto M, Ohta M, Kumakura A, Kubota M, Kumagai Y, Hamano SI, Lourenco CM, Yahaya NA, Ch'ng GS, Ngu LH, Fattal-Valevski A, Hubshman MW, Orenstein N, Marom D, Cohen L Tags: Clin Genet Source Type: research

Novel 9 amino acid in-frame deletion in the NTRK1 tyrosine kinase domain in a patient with congenital insensitivity to pain with anhydrosis.
Abstract Schematic presentation of NTRK1 protein structure. Variants identified in this study are shown in red and previously reported variants associated with CIPA are shown in black (LRM, leucine rich motif; Ig, immunoglobulin-like domain; TM, transmembrane domain; TK, tyrosine kinase domain). PMID: 28940190 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - September 21, 2017 Category: Genetics & Stem Cells Authors: Amin S, Forrester N, Norman A, Lux A, Vijayakumar K Tags: Clin Genet Source Type: research

Expanding the phenotype of DNAJC3 mutations: A case with hypothyroidism additionally to diabetes mellitus and multisystemic neurodegeneration.
Abstract Identification of this additional patient from a distant part of the originally described pedigree (Synofzik et al. 2014) confirms pathogenicity of DNAJC3 mutations. Hypothyroidism is a newly identified feature in addition to the known phenotype (diabetes with multisystemic neurodegeneration). PMID: 28940199 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - September 21, 2017 Category: Genetics & Stem Cells Authors: Bublitz SK, Alhaddad B, Synofzik M, Kuhl V, Lindner A, Freiberg C, Schmidt H, Strom TM, Haack TB, Deschauer M Tags: Clin Genet Source Type: research

Common variants in DLG1 locus are associated with non-syndromic cleft lip with or without cleft palate.
iński PP Abstract Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a common craniofacial anomaly with a complex and heterogeneous etiology. Knowledge regarding specific genetic factors underlying this birth defect is still not well understood. Therefore, we conducted an independent replication analysis for the top-associated variants located within the DLG1 locus at chromosome 3q29, which was identified as a novel cleft-susceptibility locus in our genome-wide association study (GWAS). Mega-analysis of the pooled individual data from the GWAS and replication study confirmed that common DLG1 variant...
Source: Clinical Genetics - September 19, 2017 Category: Genetics & Stem Cells Authors: Mostowska A, Gaczkowska A, Żukowski K, Ludwig KU, Hozyasz KK, Wójcicki P, Mangold E, Böhmer AC, Heilmann-Heimbach S, Knapp M, Zadurska M, Biedziak B, Budner M, Lasota A, Daktera-Micker A, Jagodziński PP Tags: Clin Genet Source Type: research

TSGA10 is a novel candidate gene associated with acephalic spermatozoa.
Abstract Acephalic spermatozoa is a rare teratozoospermia associated with male infertility. However, the pathogenesis of this disorder remains unclear. Here, we report a 27-year-old infertile male from a consanguineous family, who presented with 99% headless sperm in his ejaculate. Electron microscopic and immunofluorescence analysis suggested breakage at the midpiece of the patient's sperm cells. Subsequent whole-exome sequencing (WES) analysis identified a homozygous deletion within TSGA10 (c.211delG; p.A71Hfs*12), which resulted in the production of truncated TSGA10 protein. TSGA10 is a testis-specific protein ...
Source: Clinical Genetics - September 14, 2017 Category: Genetics & Stem Cells Authors: Sha YW, Sha YK, Ji ZY, Mei LB, Ding L, Zhang Q, Qiu PP, Lin SB, Wang X, Li P, Xu X, Li L Tags: Clin Genet Source Type: research

Management of Leigh Syndrome: current status and new insights.
Abstract Leigh syndrome (LS) is an inherited mitochondrial encephalopathy associated with gene mutations of oxidative phosphorylation(OXPHOS) pathway that result in early disability and death in affected young children. Currently, LS is incurable and unresponsive to many treatments, although some case reports indicate that supplements can improve the condition. Many novel therapies are being continuously tested in preclinical studies. In this review, we summarize the genetic basis of LS, current treatment, preclinical studies in animal models and the management of other mitochondrial diseases. Future therapeutical...
Source: Clinical Genetics - September 14, 2017 Category: Genetics & Stem Cells Authors: Chen L, Cui Y, Jiang D, Ma CY, Tse HF, Hwu WL, Lian Q Tags: Clin Genet Source Type: research

Expanding the clinical and molecular spectrum of PRMT7 mutations: three additional patients and review.
We report on three additional patients from two consanguineous families with severe/moderate intellectual disability, short stature, brachydactyly and dysmorphisms. Exome sequencing revealed two novel homozygous mutations in PRMT7. Our findings expand the clinical and molecular spectrum of homozygous PRMT7 mutations, associated to the SBIDDS syndrome, showing a possible correlation between the type of mutation and the severity of the phenotype. PMID: 28902392 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - September 13, 2017 Category: Genetics & Stem Cells Authors: Agolini E, Dentici ML, Bellacchio E, Alesi V, Radio FC, Torella A, Musacchia F, Tartaglia M, Dallapiccola B, Nigro V, Digilio MC, Novelli A Tags: Clin Genet Source Type: research

Genetic and Epigenetic Insights into Uveal Melanoma.
MC Abstract Uveal melanoma (UM) is the most frequent primary intraocular tumor in Caucasian adults and is potentially fatal if metastases develop. While several prognostic genetic changes have been identified in UM, epigenetic influences are now getting closer attention. Recent technological advances have allowed to examine the human genome to a greater extent and have improved our understanding of several diseases including malignant tumors. In this context, there has been tremendous progress in the field of UM pathogenesis. Herein, we review the literature with emphasis on genetic alterations, epigenetic modifi...
Source: Clinical Genetics - September 13, 2017 Category: Genetics & Stem Cells Authors: Sharma A, Stei MM, Fröhlich H, Holz FG, Loeffler KU, Herwig-Carl MC Tags: Clin Genet Source Type: research

Novel spondyloepimetaphyseal dysplasia due to UFSP2 gene mutation.
Abstract Beukes Hip Dysplasia is an autosomal dominant disease which has to date been described only in a large South African family of Dutch origin. The patients presented with progressive epiphyseal dysplasia limited to femoral capital epiphysis and their height was not significantly reduced. A unique variant of the ubiquitin-fold modifier 1 (Ufm1)-specific peptidase 2 (UFSP2) gene (c.868T>C) has been reported in all individuals from Beukes family with clinical and radiological diagnosis of Beukes Hip Dysplasia. Three individuals, propositus, mother, and grandmother, presented with short stature, joint pain, ...
Source: Clinical Genetics - September 11, 2017 Category: Genetics & Stem Cells Authors: Di Rocco M, Rusmini M, Caroli F, Madeo A, Bertamino M, Marre-Brunenghi G, Ceccherini I Tags: Clin Genet Source Type: research

mTOR mutations in Smith-Kingsmore syndrome: four additional patients and a review.
Martinez-Glez V, Lapunzina P Abstract Smith-Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA: 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non-neurological features. Germline or mosaic mutations of the mTOR gene have been detected in all patients. The mTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity, and the mTOR pathway (PI3K-AKT-m...
Source: Clinical Genetics - September 11, 2017 Category: Genetics & Stem Cells Authors: Gordo G, Tenorio J, Arias P, Santos-Simarro F, García-Miñaur S, Moreno JC, Nevado J, Vallespin E, Rodriguez-Laguna L, de Mena R, Dapia I, Palomares M, Del Pozo Á, Ibañez K, Silla JC, Barroso E, Ruiz Pérez VL, Martinez-Glez V, Lapunzina P Tags: Clin Genet Source Type: research

Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance.
IM, Guillen Sacoto MJ, Willaert R, Cho MT, Petrik I, Huether R, Tang S Abstract Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SETD5 phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and varia...
Source: Clinical Genetics - September 7, 2017 Category: Genetics & Stem Cells Authors: Powis Z, Farwell Hagman KD, Mroske C, McWalter K, Cohen JS, Colombo R, Serretti A, Fatemi A, David KL, Reynolds J, Immken LD, Nagakura H, Cunniff C, Payne K, Barbaro-Dieber T, Gripp KW, Baker L, Stamper T, Aleck KA, Jordan ES, Hersh J, Burton J, Wentzense Tags: Clin Genet Source Type: research

Diagnostic exome sequencing in early-onset Parkinson's disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson's disease.
Abstract Parkinson's disease (PD) is a genetically heterogeneous disorder and new putative disease genes are discovered constantly. Therefore, whole exome sequencing could be an efficient approach to genetic testing in PD. To evaluate its performance in early-onset sporadic PD, we performed diagnostic exome sequencing in 80 individuals with manifestation of PD symptoms at age 40 or earlier and a negative family history of PD. Variants in validated and candidate disease genes and risk factors for PD and atypical Parkinson syndromes were annotated, followed by further analysis for selected variants. We detected path...
Source: Clinical Genetics - September 1, 2017 Category: Genetics & Stem Cells Authors: Schormair B, Kemlink D, Mollenhauer B, Fiala O, Machetanz G, Roth J, Berutti R, Strom TM, Haslinger B, Trenkwalder C, Zahorakova D, Martasek P, Ruzicka E, Winkelmann J Tags: Clin Genet Source Type: research

Corrigendum.
Authors: PMID: 28833030 [PubMed - in process] (Source: Clinical Genetics)
Source: Clinical Genetics - August 25, 2017 Category: Genetics & Stem Cells Tags: Clin Genet Source Type: research

Bone marrow failure syndrome caused by homozygous frameshift mutation in the ERCC6L2 gene.
We report two cases of bone marrow failure with no extra-hematopoietic manifestations in patients from unrelated families with a homozygous truncating mutation in ERCC6L2. Bone marrow failure without developmental delay or microcephaly with ERCC6L2 mutation has not been previously described. PMID: 28815563 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - August 16, 2017 Category: Genetics & Stem Cells Authors: Järviaho T, Halt K, Hirvikoski P, Moilanen J, Möttönen M, Niinimäki R Tags: Clin Genet Source Type: research

Gene-panel testing of breast and ovarian cancer patients identifies a recurrent RAD51C duplication.
K, Nevanlinna H Abstract Gene-panel sequencing allows comprehensive analysis of multiple genes simultaneously and is now routinely used in clinical mutation testing of high-risk breast and ovarian cancer patients. However, only BRCA1 and BRCA2 are often analyzed also for large genomic changes. Here, we have analyzed 10 clinically relevant susceptibility genes in 95 breast or ovarian cancer patients with gene-panel sequencing including also CNV analysis for genomic changes. We identified 12 different pathogenic BRCA1, BRCA2, TP53, PTEN, CHEK2, or RAD51C mutations in 18/95 patients (19%). BRCA1/2 mutations were obs...
Source: Clinical Genetics - August 12, 2017 Category: Genetics & Stem Cells Authors: Pelttari LM, Shimelis H, Toiminen H, Kvist A, Törngren T, Borg Å, Blomqvist C, Bützow R, Couch F, Aittomäki K, Nevanlinna H Tags: Clin Genet Source Type: research

Homozygous Nonsense Mutation in SCHIP1/IQCJ-SCHIP1 Causes a Neurodevelopmental Brain Malformation Syndrome.
We report a consanguineous Arab family with three affected siblings who display a disorder of global developmental delay, learning difficulties, facial dysmorphism, hearing impairments, and cataract. The clinical phenotype was associated with characteristic brain Magnetic Resonance Imaging (MRI) features of axonal guidance defects involving anterior commissure agenesis as well as scattered areas of polymicrogyria-cobblestone complex. Whole genome sequencing revealed a novel nonsense mutation (159609921C>T) that segregated in the family consistent in an autosomal recessive pattern. This mutation located in the C-terminal...
Source: Clinical Genetics - August 8, 2017 Category: Genetics & Stem Cells Authors: Elsaid M, Chalhoub N, Ben-Omran T, Kamel H, Al Mureikhi M, Ibrahim K, Ross ME, Abdel Aleem A Tags: Clin Genet Source Type: research

Bone health and SATB2-associated syndrome.
In conclusion, low BMD, fractures, and tibial bowing are relatively common skeletal complications in individuals with SAS. DXA is a useful tool when evaluating a child with SAS suspected to have low BMD and the results might alter clinical management. PMID: 28787087 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - August 8, 2017 Category: Genetics & Stem Cells Authors: Zarate YA, Steinraths M, Matthews A, Smith W, Sun A, Wilson LC, Brain C, Allgove J, Jacobs B, Fish JL, Powell CM, Wasserman W, Van Karnebeek C, Wakeling EL, Ma NS Tags: Clin Genet Source Type: research

Diagnosis of monogenic liver diseases in childhood by Next-Generation Sequencing.
We describe our single-center experience with NGS diagnostics in standard clinical scenarios in pediatric hepatology. We investigated 135 children with suspected inherited hepatopathies, where initially no causative pathogenic variant had been identified, with an amplicon-based NGS panel of 21 genes associated with acute and chronic hepatopathies. In 23 of these patients we detected pathogenic or likely pathogenic variants in ten different genes. We present six novel variants. 14 of these patients presented with the characteristic phenotype of the related hepatopathy. Nine patients showed only few or atypical clinical symp...
Source: Clinical Genetics - August 4, 2017 Category: Genetics & Stem Cells Authors: Stalke A, Skawran B, Auber B, Illig T, Schlegelberger B, Junge N, Goldschmidt I, Leiskau C, von Neuhoff N, Baumann U, Pfister ED Tags: Clin Genet Source Type: research

A case of atypical Kabuki syndrome arising from a novel missense variant in HNRNPK.
Abstract A novel causative variant (c. 464T>C, p.Leu155Pro) in the heterogeneous nuclear ribonucleoprotein K (HNRNPK) gene. PMID: 28771707 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - August 3, 2017 Category: Genetics & Stem Cells Authors: Miyake N, Inaba M, Mizuno S, Shiina M, Imagawa E, Miyatake S, Nakashima M, Mizuguchi T, Takata A, Ogata K, Matsumoto N Tags: Clin Genet Source Type: research

Mosaic intragenic deletion of FBN2 and severe congenital contractural arachnodactyly.
oi JP PMID: 28762477 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - August 1, 2017 Category: Genetics & Stem Cells Authors: Lavillaureix A, Heide S, Chantot-Bastaraud S, Marey I, Keren B, Grigorescu R, Jouannic JM, Gelot A, Whalen S, Héron D, Siffroi JP Tags: Clin Genet Source Type: research

Mechanisms of Mendelian dominance.
Abstract Genetic dominance has long been considered as a qualitative reflection of interallelic interactions. Dominance arises from many multiple sources whose unifying theme is the existence of non-linear relationships between the genotypic and phenotypic values. One of the clearest examples are dominant negative mutations (DNMs) in which a defective subunit poisons a macromolecular complex. Dominance can also be due to the presence of a heterozygous null allele, as is the case of haploinsufficiency. Dominance can also be influenced by epistatic (interloci) interactions. For instance, a pre-existing genetic varia...
Source: Clinical Genetics - July 28, 2017 Category: Genetics & Stem Cells Authors: Veitia RA, Caburet S, Birchler JA Tags: Clin Genet Source Type: research

Association of combined GIF290T > C heterozygous mutation/FUT2 secretor variant with neural tube defects.
Association of combined GIF290T>C heterozygous mutation/FUT2 secretor variant with neural tube defects. Clin Genet. 2017 Jul 25;: Authors: Guéant-Rodriguez RM, Chery C, Fofou-Caillierez BM, Voirin J, Foliguet B, Josse T, Tramoy D, François F, Guéant JL Abstract Folate and vitamin B12 are needed for the proper embryo-fetal development possibly through their interacting role in the one-carbon metabolism. Folate fortification reduces the prevalence of complex birth defects, and more specifically neural tube defects (NTD). GIF and FUT2 are two genes associated with the uptake and b...
Source: Clinical Genetics - July 25, 2017 Category: Genetics & Stem Cells Authors: Guéant-Rodriguez RM, Chery C, Fofou-Caillierez BM, Voirin J, Foliguet B, Josse T, Tramoy D, François F, Guéant JL Tags: Clin Genet Source Type: research

Unilateral Vestibular Schwannoma and Meningiomas in a Patient with PIK3CA-Related Segmental Overgrowth: Co-occurrence of Mosaicism for Two Rare Disorders.
Abstract A 28-year-old female with PIK3CA-related segmental overgrowth presented with headaches. She also had a unilateral vestibular schwannoma (VS), as well as three small (A (p.Gly914Arg) mutation, confirming the diagnosis of PIK3CA-related overgrowth, but no mutations in NF2 were detected. Although VS has not previously been reported in PIK3CA-related segmental overgrowth, meningiomas have, raising the question of whether this patient's VS and meningiomas represent coincidental NF2 or phenotypic extension of her overgrowth syndrome. Genetic analysis of the VS revealed a heterozygous NF2 mutation c.784C>T (p...
Source: Clinical Genetics - July 24, 2017 Category: Genetics & Stem Cells Authors: Mills JR, Moyer AM, Kipp BR, Poplawski AB, Messiaen LM, Babovic-Vuksanovic D Tags: Clin Genet Source Type: research

Novel non-neutral mitochondrial DNA mutations found in childhood acute lymphoblastic leukemia.
ri A, Uusimaa J Abstract Mitochondria produce adenosine triphosphate (ATP) for energy requirements via the mitochondrial oxidative phosphorylation (OXPHOS) system. One of the hallmarks of cancer is the energy shift towards glycolysis. Low OXPHOS activity and increased glycolysis are associated with aggressive types of cancer. Mitochondria have their own genome (mtDNA) encoding for 13 essential subunits of the OXPHOS enzyme complexes. We studied mtDNA in childhood acute lymphoblastic leukemia (ALL) to detect potential pathogenic mutations in OXPHOS complexes. The whole mtDNA from blood and bone marrow samples at di...
Source: Clinical Genetics - July 14, 2017 Category: Genetics & Stem Cells Authors: Järviaho T, Hurme-Niiranen A, Soini HK, Niinimäki R, Möttönen M, Savolainen ER, Hinttala R, Harila-Saari A, Uusimaa J Tags: Clin Genet Source Type: research

Whole-exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: outcomes from a cohort of 50 families.
This study highlights the use of WES in the molecular diagnostic approach of highly heterogeneous disorders, such as IPNs, places it in context of other published neuropathy cohorts, while further highlighting associated benefits for discovery. PMID: 28708278 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - July 14, 2017 Category: Genetics & Stem Cells Authors: Hartley T, Wagner JD, Warman-Chardon J, Tétreault M, Brady L, Baker S, Tarnopolsky M, Bourque PR, Parboosingh JS, Smith C, McInnes B, Innes AM, Bernier F, Curry CJ, Yoon G, Horvath GA, Bareke E, FORGE Canada Consortium, Care4Rare Canada Consortium, Majew Tags: Clin Genet Source Type: research

Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.
In this study, we report the experience of two clinical genetic centers using medical exome for diagnosis of neurodevelopmental disorders. We recruited 216 consecutive index patients with neurodevelopmental disorders in two French genetic centers, corresponded to the daily practice of the units and included non-syndromic intellectual disability (n=33), syndromic intellectual disability (n=122), pediatric neurodegenerative disorders (n=7) and autism spectrum disorder (n=54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely path...
Source: Clinical Genetics - July 14, 2017 Category: Genetics & Stem Cells Authors: Chérot E, Keren B, Dubourg C, Carré W, Fradin M, Lavillaureix A, Afenjar A, Burglen L, Whalen S, Charles P, Marey I, Heide S, Jacquette A, Heron D, Doummar D, Rodriguez D, Billette de Villemeur T, Moutard ML, Guët A, Xavier J, Périsse D, Cohen D, Demu Tags: Clin Genet Source Type: research

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