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p.D313Y is more than just a polymorphism in Fabry disease.
PMID: 29740824 [PubMed - in process] (Source: Clinical Genetics)
Source: Clinical Genetics - May 10, 2018 Category: Genetics & Stem Cells Authors: du Moulin M, Muschol N Tags: Clin Genet Source Type: research

EAST/SeSAME syndrome - review of the literature and introduction of four new Latvian patients.
Abstract EAST (Epilepsy, Ataxia, Sensorineural deafness, Tubulopathy) or SeSAME (Seizures, Sensorineural deafness, Ataxia, Mental retardation, and Electrolyte imbalance) syndrome is a rare autosomal recessive syndrome first described in 2009 independently by Bockenhauer and Scholl. It is caused by mutations in KCNJ10, which encodes Kir4.1, an inwardly rectifying K+ channel found in the brain, inner ear, kidney and eye. To date, 16 mutations in at least 28 patients have been reported. In this paper, we review mutations causing EAST/SeSAME syndrome, clinical manifestations in detail, and efficacy of treatment in pre...
Source: Clinical Genetics - May 3, 2018 Category: Genetics & Stem Cells Authors: Marta C, Ieva M, Inna I, Mareta A, Sandra K, Pereca J, Janis S, Dita P, Jurgis S Tags: Clin Genet Source Type: research

Atrioventricular canal defect and genetic syndromes: The unifying role of Sonic Hedgehog.
Abstract The atrioventricular canal defect (AVCD) is a congenital heart defect (CHD) frequently associated with extracardiac anomalies (75%). Previous observations from a personal series of patients with AVCD and "polydactyly syndromes" demonstrated that the distinct morphology and combination of AVCD features in some of these syndromes is reminiscent of the cardiac phenotype found in heterotaxy, a malformation complex previously associated with functional cilia abnormalities and aberrant Hedgehog (Hh) signaling. Hh signaling coordinates multiple aspects of left-right lateralization and cardiovascular gr...
Source: Clinical Genetics - May 3, 2018 Category: Genetics & Stem Cells Authors: Digilio MC, Pugnaloni F, De Luca A, Calcagni G, Baban A, Dentici ML, Versacci P, Dallapiccola B, Tartaglia M, Marino B Tags: Clin Genet Source Type: research

Discovery of four exonic and one intergenic novel susceptibility loci for leprosy.
Abstract Seven new risk coding variants have been identified through an exome-wide association study (EWAS), which studied the contributions of protein-coding variants to leprosy susceptibility. But some potential susceptibility loci were not studied in the previous EWAS study because of the project consideration. Seventeen unstudied potential susceptibility loci of the previous EWAS were validated in 3,169 cases and 9,814 controls in this study. Four disease associated exonic loci were identified: rs671 in ALDH2 (P = 2.0 × 10-20 , odds ratio (OR) = 1.35), rs13259978 in SLC7A2 (P = 1.74 × 10-8 , OR = 1...
Source: Clinical Genetics - May 3, 2018 Category: Genetics & Stem Cells Authors: Wang Z, Mi Z, Wang H, Sun L, Yu G, Fu X', Wang C, Bao F, Yue Z, Zhao Q, Wang N, Cheng X, Liu H, Zhang F Tags: Clin Genet Source Type: research

Correction to: Reassessing the clinical spectrum associated with Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome in French FH mutation carriers.
PMID: 29655270 [PubMed - in process] (Source: Clinical Genetics)
Source: Clinical Genetics - April 17, 2018 Category: Genetics & Stem Cells Authors: Muller M, Guillaud-Bataille M, Richard S, Benusiglio PR Tags: Clin Genet Source Type: research

Correction to: PUGS: A novel scale to assess perceptions of uncertainties in genome sequencing.
PMID: 29655271 [PubMed - in process] (Source: Clinical Genetics)
Source: Clinical Genetics - April 17, 2018 Category: Genetics & Stem Cells Authors: Biesecker BB, Woolford SW, Klein WMP, Brothers KB, Umstead KL, Lewis KL, Biesecker LG, Han PKJ Tags: Clin Genet Source Type: research

Erratum.
Authors: PMID: 29655272 [PubMed - in process] (Source: Clinical Genetics)
Source: Clinical Genetics - April 17, 2018 Category: Genetics & Stem Cells Tags: Clin Genet Source Type: research

Polymorphisms of genes involved in inflammation and blood vessel development influence the risk of varicose veins.
Abstract Heredity plays an important role in the etiology of varicose veins (VVs). However, the genetic basis underlying this condition remains poorly understood. Our aim was to replicate top association signals from genome-wide association studies (GWAS) for VVs of lower extremities using two independent datasets - our sample of ethnic Russian individuals (709 cases and 278 controls) and a large cohort of British residents from UK Biobank (10,861 cases and 397,594 controls). Associations of polymorphisms rs11121615, rs6712038, rs507666, rs966562, rs7111987, rs6062618, and rs6905288 were validated in the UK Bioban...
Source: Clinical Genetics - April 16, 2018 Category: Genetics & Stem Cells Authors: Shadrina A, Tsepilov Y, Smetanina M, Voronina E, Seliverstov E, Ilyukhin E, Kirienko A, Zolotukhin I, Filipenko M Tags: Clin Genet Source Type: research

Genetic variant spectrum in 265 Chinese patients with hemophagocytic lymphohistiocytosis: molecular analyses of PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP.
This study aimed to investigate the frequencies and distributions of inherited variants in PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP genes in Chinese patients with HLH. A total of 265 patients diagnosed with HLH from January 2010 to December 2016 were recruited and analyzed for the six genes. Genetic variants were observed in 87 (32.83%) patients. 36 (13.58%) exhibited variants in UNC13D, 18 (6.79%) exhibited PRF1 variants, 10 (3.77%) had variants in XIAP, 9 (3.40%) exhibited variants in STXBP2, 6 (2.26%) carried variants in SH2D1A, 1 (0.38%) had STX11 variant, and 7 (2.64%) exhibited digenic variants. Monoallelic vari...
Source: Clinical Genetics - April 14, 2018 Category: Genetics & Stem Cells Authors: Chen X, Wang F, Zhang Y, Teng W, Wang M, Nie D, Zhou X, Wang D, Zhao H, Zhu P, Liu H Tags: Clin Genet Source Type: research

Systematic reanalysis of genomic data improves quality of variant interpretation.
Abstract As genomic sequencing expands, so does our knowledge of the link between genetic variation and disease. Deeper catalogs of variant frequencies improve identification of benign variants, while sequencing affected individuals reveals disease-associated variation. Accumulation of human genetic data thus makes reanalysis a means to maximize benefits of clinical sequencing. We implemented pipelines to systematically reassess sequencing data from 494 individuals with developmental disability. Reanalysis yielded pathogenic or likely pathogenic (P/LP) variants in six individuals who initially had no P/LP variants...
Source: Clinical Genetics - April 13, 2018 Category: Genetics & Stem Cells Authors: Hiatt SM, Amaral MD, Bowling KM, Finnila CR, Thompson ML, Gray DE, Lawlor JMJ, Cochran JN, Bebin EM, Brothers KB, East KM, Kelley WV, Lamb NE, Levy SE, Lose EJ, Neu MB, Rich CA, Simmons S, Myers RM, Barsh GS, Cooper GM Tags: Clin Genet Source Type: research

Expanding the clinical spectrum of biallelic ZNF335 variants.
We describe herein two additional affected individuals with biallelic ZNF335 variants, one individual with a homozygous c.1399T>C, p.(Cys467Arg) variant, and a second individual with compound heterozygous c.2171_2173delTCT, p.(Phe724del) and c.3998A>G, p.(Glu1333Gly) variants in ZNF335; with the latter variant predicted to affect splicing. Whereas the first case presented with early death and a severe phenotype characterized by anterior agyria with prominent extra-axial spaces, absent basal ganglia, and hypoplasia of the brainstem and cerebellum, the second case had a milder clinical presentation with hypomyelination...
Source: Clinical Genetics - April 13, 2018 Category: Genetics & Stem Cells Authors: Stouffs K, Stergachis AB, Vanderhasselt T, Dica A, Janssens S, Vandervore L, Gheldof A, Bodamer O, Keymolen K, Seneca S, Liebaers I, Jayaraman D, Hill HE, Partlow JN, Walsh CA, Jansen AC Tags: Clin Genet Source Type: research

TASP1 is deleted in an infant with developmental delay, microcephaly, distinctive facial features, and multiple congenital anomalies.
We report a 20p12.1 homozygous deletion including exons 5-10 of the TASP1 gene in an infant with developmental delay, acquired microcephaly, distinctive facial features, and multiple congenital anomalies involving skeletal, cardiac, and renal systems. TASP1 encodes taspase 1 which is responsible for cleaving, thus activating, a number of transcription factors including the mixed lineage leukemia 1 (MLL1). Taspase 1-deficient mice demonstrated early lethality, skeletal abnormalities, and growth failure, which supports a potentially causal role of TASP1 deletion in this infant. Furthermore, the infant reported here had many ...
Source: Clinical Genetics - April 6, 2018 Category: Genetics & Stem Cells Authors: Suleiman J, Mundt M, Sampath S, El-Hattab AW Tags: Clin Genet Source Type: research

Corrigendum.
Authors: PMID: 29537094 [PubMed - in process] (Source: Clinical Genetics)
Source: Clinical Genetics - March 23, 2018 Category: Genetics & Stem Cells Tags: Clin Genet Source Type: research

Corrigendum.
Authors: PMID: 29537095 [PubMed - in process] (Source: Clinical Genetics)
Source: Clinical Genetics - March 23, 2018 Category: Genetics & Stem Cells Tags: Clin Genet Source Type: research

Splice-site mutations in VEGFC cause loss of function and Nonne-Milroy-like primary lymphedema.
ula M PMID: 29542815 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - March 15, 2018 Category: Genetics & Stem Cells Authors: Fastré E, Lanteigne LE, Helaers R, Giacalone G, Revencu N, Dionyssiou D, Demiri E, Brouillard P, Vikkula M Tags: Clin Genet Source Type: research

Hypercalciuria and nephrolithiasis: Expanding the renal phenotype of Donnai-Barrow syndrome.
Abstract Whole exome sequencing detected novel likely pathogenic variants in LRP2 gene in 2 patients presenting with hearing and vision loss, and the Dent disease (DD) classical renal phenotype, that is, low molecular weight proteinuria (LMWP), hypercalciuria and nephrocalcinosis/nephrolithiasis. We propose that a subset of patients presenting as DD may represent unrecognized cases or mild forms of Donnai-Barrow/facio-oculo-acustico-renal (DB/FOAR) syndrome or be on the phenotypic continuum between the 2 conditions. PMID: 29532936 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - March 13, 2018 Category: Genetics & Stem Cells Authors: Anglani F, Terrin L, Brugnara M, Battista M, Cantaluppi V, Ceol M, Bertoldi L, Valle G, Joy MP, Pober BR, Longoni M Tags: Clin Genet Source Type: research

Kidney enlargement and multiple liver cyst formation implicate mutations in PKD1/2 in adult sporadic polycystic kidney disease.
Abstract Distinguishing autosomal dominant polycystic kidney disease (ADPKD) from other inherited renal cystic diseases in patients with adult polycystic kidney disease and no family history is critical for correct treatment and appropriate genetic counseling. However, for patients with no family history, there are no definitive imaging findings that provide an unequivocal ADPKD diagnosis. We analyzed 53 adult polycystic kidney disease patients with no family history. Comprehensive genetic testing was performed using capture-based next-generation sequencing for 69 genes currently known to cause hereditary renal cy...
Source: Clinical Genetics - March 9, 2018 Category: Genetics & Stem Cells Authors: Fujimaru T, Mori T, Sekine A, Mandai S, Chiga M, Kikuchi H, Ando F, Mori Y, Nomura N, Iimori S, Naito S, Okado T, Rai T, Hoshino J, Ubara Y, Uchida S, Sohara E Tags: Clin Genet Source Type: research

The D313Y genotype-Pathogenic mutation or polymorphism?
PMID: 29521444 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - March 9, 2018 Category: Genetics & Stem Cells Authors: Oder D, Wanner C, Nordbeck P Tags: Clin Genet Source Type: research

EFNB2 haploinsufficiency causes a syndromic neurodevelopmental disorder.
We report a patient with a de novo variant in EFNB2 and a family in which segregates a 610-kb deletion at chromosome 13q33 encompassing only ARGLU1 and EFNB2 genes. The de novo variant was observed in a patient with anal stenosis, hypoplastic left ventricle and mild developmental delay. The deletion was identified in 2 sibs with congenital heart defect and mild developmental delay. One of the affected sibs further had myoclonic epilepsy and bilateral sensorineural hearing loss. The carrier mother was apparently asymptomatic. Because EFNB2 is located in the subtelomeric region of 13q chromosome, we reviewed the previous rep...
Source: Clinical Genetics - March 6, 2018 Category: Genetics & Stem Cells Authors: Lévy J, Haye D, Marziliano N, Casu G, Guimiot F, Dupont C, Teissier N, Benzacken B, Gressens P, Pipiras E, Verloes A, Tabet AC Tags: Clin Genet Source Type: research

Unexpected diagnosis of a SHH nonsense variant causing a variable phenotype ranging from familial coloboma and Intellectual disability to isolated microcephaly.
net C PMID: 29498412 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - March 2, 2018 Category: Genetics & Stem Cells Authors: Bruel AL, Thevenon J, Huet F, Jean-Marcais N, Odent S, Dubourg C, Lehalle D, Tran Mau-Them F, Philippe C, Moutton S, Houcinat N, Gay S, Guibaud L, Duffourd Y, Rivière JB, Faivre L, Thauvin-Robinet C Tags: Clin Genet Source Type: research

Rare compound heterozygous variants in PNKP identified by whole exome sequencing in a German patient with ataxia-oculomotor apraxia 4 and pilocytic astrocytoma.
Abstract Ataxia-oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive neurologic disorder. The phenotype is characterized by ataxia, oculomotor apraxia, peripheral neuropathy and dystonia. AOA4 is caused by biallelic pathogenic variants in the PNKP gene encoding a polynucleotide kinase 3'-phosphatase with an important function in DNA-damage repair. By whole exome sequencing, we identified 2 variants within the PNKP gene in a 27-year-old German woman with a clinical AOA phenotype combined with a cerebellar pilocytic astrocytoma diagnosed at 23 years of age. One variant, a duplication in exon 14 resulting i...
Source: Clinical Genetics - March 2, 2018 Category: Genetics & Stem Cells Authors: Scholz C, Golas MM, Weber RG, Hartmann C, Lehmann U, Sahm F, Schmidt G, Auber B, Sturm M, Schlegelberger B, Illig T, Steinemann D, Hofmann W Tags: Clin Genet Source Type: research

ZNF687 mutations are frequently found in pagetic patients from South Italy: implication in the pathogenesis of Paget's disease of bone.
Abstract Paget's disease of bone (PDB) is a skeletal disorder whose molecular basis are not fully elucidated. However, 10% of patients show a familial PDB and 35% of them carry mutations in the SQSTM1 gene. We recently reported a founder mutation (p.Pro937Arg) in the ZNF687 gene, underlying PDB complicated by Giant Cell Tumor (GCT/PDB) and rarely occurring in PDB patients without neoplastic degeneration. Since 80% of Italian GCT/PDB patients derive from Avellino, we hypothesized that ZNF687 mutation rate was higher in this region than elsewhere. Interestingly, our molecular analysis on 30 PDB patients showed that ...
Source: Clinical Genetics - March 1, 2018 Category: Genetics & Stem Cells Authors: Divisato G, di Carlo FS, Petrillo N, Esposito T, Gianfrancesco F Tags: Clin Genet Source Type: research

2p24.2 (rs7552) is a susceptibility locus for nonsyndromic cleft lip with or without cleft palate in the Brazilian population.
ta RD Abstract The population of Brazil is highly admixed, with each individual showing variable levels of Amerindian, European and African ancestry, which may interfere in the genetic susceptibility of known risk loci to nonsyndromic cleft lip with or without cleft palate (NSCL±P). Here we investigated 5 reported genome-wide loci for NSCL±P in an ancestry-structured case-control study containing 1,697 Brazilian participants (831 NSCL±P and 866 healthy controls). SNPs rs7552 in 2q24.2, rs8049367 in 16p13.3, rs1880646, rs7406226, rs9891446 in 17p13, rs1588366 in 17q23.2 and rs73039426 in 19q13....
Source: Clinical Genetics - February 28, 2018 Category: Genetics & Stem Cells Authors: Machado RA, Nogueira EN, Martelli-Júnior H, Reis SR, Persuhn DC, Coletta RD Tags: Clin Genet Source Type: research

Regulatory network analysis of LINC00472, a long noncoding RNA downregulated by DNA hypermethylation in colorectal cancer.
Abstract Colorectal cancer (CRC), one of the common malignant cancers in the world, is caused by accumulated alterations of genetic and epigenetic factors over a long period of time. Along with that protein-coding genes being identified as oncogenes or tumor suppressors in CRC, a number of lncRNAs have also been found to be associated with CRC. Considering the important regulatory role of lncRNAs, the first goal of this study was to identify CRC-associated lncRNAs from a public database. One such lncRNA, LINC00472, was verified to be downregulated in CRC cell lines and cancer tissues compared with adjacent tissues...
Source: Clinical Genetics - February 28, 2018 Category: Genetics & Stem Cells Authors: Chen L, Zhang W, Li DY, Wang X, Tao Y, Zhang Y, Dong C, Zhao J, Zhang L, Zhang X, Guo J, Zhang X, Liao Q Tags: Clin Genet Source Type: research

CKAP2L mutation confirms the diagnosis of Filippi syndrome.
o S PMID: 29473684 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - February 23, 2018 Category: Genetics & Stem Cells Authors: Capecchi G, Baldassarri M, Ferranti S, Guidoni E, Cioni M, Nürnberg P, Mencarelli MA, Renieri A, Grosso S Tags: Clin Genet Source Type: research

Molecular and clinical studies in eight patients with Temple syndrome.
Abstract Temple syndrome (TS14, #616222) is a rare imprinting disorder characterised by phenotypic features including pre- and postnatal growth retardation, muscular hypotonia and feeding difficulties in infancy, early puberty and short stature with small hands and feet and often truncal obesity. It is caused by maternal uniparental disomies, paternal deletions and primary imprinting defects that affect the chromosomal region 14q32 and lead to a disturbed expression of imprinted genes in this region. Here we present detailed clinical data of eight patients with Temple syndrome, four with an imprinting defect, two ...
Source: Clinical Genetics - February 22, 2018 Category: Genetics & Stem Cells Authors: Gillessen-Kaesbach G, Albrecht B, Eggermann T, Elbracht M, Mitter D, Morlot S, van Ravenswaaij-Arts CMA, Schulz S, Strobl-Wildemann G, Buiting K, Beygo J Tags: Clin Genet Source Type: research

Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.
el TR, Laurence F Abstract Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in OMIM genes and non-OMIM genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients, in order to identity novel MH-ID genes. Only DLG4 gene met these criteria. D...
Source: Clinical Genetics - February 20, 2018 Category: Genetics & Stem Cells Authors: Sébastien M, Ange-Line B, Mirna A, Martin C, Elisabeth S, Cyril G, Anne-Marie G, Aude C, Perrine C, Delphine H, Anne F, Nada H, Antonio V, Frédéric TM, Christophe P, Yannis D, Christel TR, Laurence F Tags: Clin Genet Source Type: research

Expanding the histopathological spectrum of CFL2-related myopathies.
Abstract Congenital myopathies (CMs) caused by mutation in cofilin-2 gene (CFL2) show phenotypic heterogeneity ranging from early onset and rapid progressive forms to milder myopathy. Muscle histology is also heterogeneous showing rods and /or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss-of-function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2-/-...
Source: Clinical Genetics - February 19, 2018 Category: Genetics & Stem Cells Authors: Fattori F, Fiorillo C, Rodolico C, Tasca G, Verardo M, Bellacchio E, Pizzi S, Ciolfi A, Fagiolari G, Lupica A, Broda P, Pedemonte M, Moggio M, Bruno C, Tartaglia M, Bertini E, D'Amico A Tags: Clin Genet Source Type: research

Genetic Investigation of 93 Families with Microphthalmia or Posterior Microphthalmos.
Majid S, Aldahmesh MA, Alkuraya FS Abstract Microphthalmia is a developmental eye defect that is highly variable in severity and in its potential for systemic association. Despite the discovery of many disease genes in microphthalmia, at least 50% of patients remain undiagnosed genetically. Here, we describe a cohort of 147 patients (93 families) from our highly consanguineous population with various forms of microphthalmia (including the distinct entity of posterior microphthalmos) that were investigated using a next-generation sequencing multi-gene panel (i-panel) as well as whole exome sequencing (WES) and mole...
Source: Clinical Genetics - February 16, 2018 Category: Genetics & Stem Cells Authors: Patel N, Khan AO, Alsahli S, Abdel-Salam G, Nowilaty SR, Mansour AM, Nabil A, Al-Owain M, Sogati S, Salih MA, Kamal AM, Alsharif H, Alsaif H, Alzahrani SS, Abdulwahab F, Ibrahim N, Hashem M, Faquih T, Shah ZA, Abouelhoda M, Monies D, Dasouki M, Shaheen R, Tags: Clin Genet Source Type: research

INTU-related oral-facial-digital syndrome type VI: a confirmatory report.
This report of a second patient with INTU-related OFD and the further delineation of its neuroimaging and skeletal phenotype now allow INTU-related OFD to be classified within the OFD VI group. Patients display a phenotype similar to that of mice with a hypomorphic mutation of Intu, but with the addition of a heart defect. PMID: 29451301 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - February 16, 2018 Category: Genetics & Stem Cells Authors: Bruel AL, Levy J, Elenga N, Defo A, Favre A, Lucron H, Capri Y, Perrin L, Passemard S, Vial Y, Tabet AC, Faivre L, Thauvin-Robinet C, Verloes A Tags: Clin Genet Source Type: research

A B3GALT6 variant in patient originally described as Al-Gazali syndrome and implicating the ER quality control in the mechanism of some β3GalT6-pathy mutations.
We report a disease-causing variant c.618C>G, p.(Cys206Trp) in one patient originally described as Al-Gazali syndrome and reported in 1999. We evaluated the involvement of the Endoplasmic-reticulum-associated protein degradation (ERAD), in the pathogenesis of thirteen B3GALT6 variants. Retention in ER was evident in six of them while the c.618C>G, p.(Cys206Trp) and the other six variants trafficked normally. Our findings confirm the involvement of B3GALT6 in the pathogenesis of Al-Gazali syndrome and suggest that Al-Gazali syndrome represents the severe end of the spectrum of the phenotypes caused by pathogenic varia...
Source: Clinical Genetics - February 14, 2018 Category: Genetics & Stem Cells Authors: Ben-Mahmoud A, Ben-Salem S, Al-Sorkhy M, John A, Ali BR, Al-Gazali L Tags: Clin Genet Source Type: research

Exome sequencing reveals three homozygous missense variants in SNRPA in two sisters with syndromic intellectual disability.
We describe the previously unreported concurrence of intellectual disability, short stature, poor speech, and minor craniofacial and hand anomalies in two female siblings with three homozygous missense variants in SNRPA (a component of the U1 small nuclear ribonucleoprotein complex) characterized by homozygosity mapping and whole exome sequencing. Combined, c.97A>G, c.98T>C, and c.100T>A, in exon 2 of SNRPA lead to p.Ile33Ala and p.Phe34Ile exchanges, which were predicted in silico to be deleterious. Although both patients exhibited some clinical features seen in other spliceosomal disorders, their complete clinic...
Source: Clinical Genetics - February 13, 2018 Category: Genetics & Stem Cells Authors: Rangel-Sosa MM, Figuera-Villanueva LE, González-Ramos IA, Pérez-Páramo YX, Martínez-Jacobo LA, Arnaud-López L, Nastasi-Catanese JA, Rivas-Estilla AM, Galán-Huerta KA, Rojas-Martínez A, Ortiz-López R, Córdova-Fletes C Tags: Clin Genet Source Type: research

Cancer gene-panel testing identifies two loss-of-function alleles in PALB2 and PTEN.
Abstract Synchronous loss-of-function mutations in the cancer predisposing genes, PTEN and PALB2 identified by multigene panel. PMID: 29430632 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - February 11, 2018 Category: Genetics & Stem Cells Authors: Avgerinou C, Fostira F, Economopoulou P, Psyrri A Tags: Clin Genet Source Type: research

Characteristics of genetic diseases in consanguineous populations in the genomic era: lessons from Arab communities in North Israel.
Abstract The health outcome of consanguineous/endogamous unions is an increased risk of autosomal recessive disorders in their progeny. This manuscript is focused on consanguineous/endogamous populations living in North Israel. Molecular tools show that spouses' relatedness and hence their risks for congenital diseases among offspring are often greater than the risk calculated on the basis of reported pedigrees. Revealing founder mutations allows for effective genetic counseling, but also induces genetic screening of the whole community in case the mutations are found to be frequent. More complex genetic mechanism...
Source: Clinical Genetics - February 10, 2018 Category: Genetics & Stem Cells Authors: Shalev SA Tags: Clin Genet Source Type: research

Intrafamiliar clinical variability of Circumferential Skin Creases Kunze Type caused by a novel heterozygous mutation of N-terminal TUBB gene.
We report a 9-year-old boy with a diagnosis of CSC-KT based on MTBS, facial dysmorphism, microcephaly, severe ID, cortical atrophy and corpus callosum hypoplasia. Sanger sequencing identified a novel heterozygous c.218T>C (p.Met73Thr) mutation in the N-terminal of TUBB gene, that was inherited from the mother affected by isolated MTBS. This is the first report of inherited TUBB gene-related CSC-KT resulting from a novel heterozygous mutation in the N-terminal domain. Present data support the role of TUBB mutations in CSC-KT and definitely includes CSC-KT syndrome within the tubulinopathies. PMID: 29427453 [PubMed -...
Source: Clinical Genetics - February 10, 2018 Category: Genetics & Stem Cells Authors: Dentici ML, Terracciano A, Bellacchio E, Capolino R, Novelli A, Digilio MC, Dallapiccola B Tags: Clin Genet Source Type: research

Identification of a novel lethal form of autosomal recessive ichthyosis caused by UDP-glucose ceramide glucosyltransferase deficiency.
PMID: 29417556 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - February 8, 2018 Category: Genetics & Stem Cells Authors: Monies D, Anabrees J, Ibrahim N, Elbardisy H, Abouelhoda M, Meyer BF, Alkuraya FS Tags: Clin Genet Source Type: research

Rare, genetically conditioned forms of rickets - differential diagnosis and advances in diagnostics and treatment.
Abstract Apart from the classic forms of rickets, there are rare genetic disorders from the group of vitamin D-resistant rickets where the clinical picture is very similar to the classic forms. Diagnosis of genetically conditioned rickets is often delayed. It is very important to know that a disorder of genetic background may be the cause of the failure of classic treatment in patients with rachitic symptoms. In the group of genetically conditioned rickets there are, among others, congenital hypophosphatemic rickets and vitamin D-dependent rickets type I and II. Congenital hypophosphatemic rickets is characterised...
Source: Clinical Genetics - February 8, 2018 Category: Genetics & Stem Cells Authors: Michałus I, Rusińska A Tags: Clin Genet Source Type: research

Genetic and Clinical Findings in a Chinese Cohort of Patients with collagen VI-Related Myopathies.
Abstract Collagen VI-related myopathy, caused by pathogenic variants in the genes encoding collagen VI, represents a clinical continuum from Ullrich congenital muscular dystrophy (UCMD) to Bethlem myopathy (BM). Clinical data of 60 probands and their family members were collected and muscle biopsies of 26 patients were analyzed. COL6A1, COL6A2 and COL6A3 exons were analyzed by direct sequencing or next generation sequencing (NGS). Sixty patients were characterized by delayed motor milestones, muscle weakness, skin and joint changes with forty UCMD and twenty BM. Muscle with biopsies revealed dystrophic changes and...
Source: Clinical Genetics - February 8, 2018 Category: Genetics & Stem Cells Authors: Fan Y, Liu A, Wei C, Yang H, Chang X, Wang S, Yuan Y, Bonnemann C, Wu Q, Wu X, Xiong H Tags: Clin Genet Source Type: research

Phenotypic Characterization of KCTD3-related Developmental Epileptic Encephalopathy.
In this report, we describe the clinical phenotype associated with two pathogenic variants in KCTD3 gene. Seven individuals (including one set of monozygotic twin) from four consanguineous families presented with developmental epileptic encephalopathy, global developmental delay, central hypotonia, progressive peripheral hypertonia, and variable dysmorphic facial features. Posterior fossa abnormalities (ranging from Dandy-Walker malformation to isolated hypoplasia of the cerebellar vermis) were consistently observed in addition to other variable neuroradiological abnormalities such as hydrocephalus and abnormal brain myeli...
Source: Clinical Genetics - February 6, 2018 Category: Genetics & Stem Cells Authors: Faqeih EA, Almannai M, Saleh MM, AlWadie AH, Samman MM, Alkuraya FS Tags: Clin Genet Source Type: research

Prenatal detection of uniparental disomy of chromosome 2 carrying a CHRND pathogenic variant that causes lethal multiple pterygium syndrome.
PMID: 29399782 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - February 5, 2018 Category: Genetics & Stem Cells Authors: Shen W, Young BA, Bosworth M, Wright KE, Lamb AN, Ji Y Tags: Clin Genet Source Type: research

Novel NALCN biallelic truncating mutations in siblings with IHPRF1 syndrome.
Abstract Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. It is caused by mutations in the NALCN gene that encodes a voltage-independent, cation channel permeable to NM, K+ and Ca2+ and forms a channel complex with UNCSO and UNC79. So far, only 4 homozygous mutations have been found in 11 cases belonging to 4 independent consanguineous families. We studied a Sardinian family with 2 siblings presenting dysmorphic facies, hypotonia, psychomotor retardation, epilepsy, absent speech, sleep ...
Source: Clinical Genetics - February 5, 2018 Category: Genetics & Stem Cells Authors: Angius A, Cossu S, Uva P, Oppo M, Onano S, Persico I, Fotia G, Atzeni R, Cuccuru G, Asunis M, Cucca F, Pruna D, Crisponi L Tags: Clin Genet Source Type: research

SAAMP 2.0: an algorithm to predict genotype-phenotype correlation of lysosomal storage diseases.
Abstract Lysosomal storage diseases (LSDs) are a group of genetic disorders, resulting from deficiencies of lysosomal enzyme. Genotype-phenotype correlation is essential for timely and proper treatment allocation. Recently, by integrating prediction outcomes of 7 bioinformatics tools, we developed a SAAMP algorithm to predict the impact of individual amino acid substitution. To optimize this approach, we evaluated the performance of these bioinformatics tools in a broad array of genes. PolyPhen and PROVEAN had the best performances, while SNP&GOs, PANTHER and I-Mutant had the worst performances. Therefore, SAA...
Source: Clinical Genetics - February 2, 2018 Category: Genetics & Stem Cells Authors: Ou L, Przybilla MJ, Whitley CB Tags: Clin Genet Source Type: research

De novo variants in CDK13 associated with syndromic ID/DD; molecular and clinical delineation of 15 individuals and a further review.
, Stegmann APA, de Vries BBA, Schuurs-Hoeijmakers JHM Abstract De novo variants in the gene encoding cyclin-dependent kinase 13 (CDK13) have been associated with congenital heart defects and intellectual disability (ID). Here, we present the clinical assessment of fifteen individuals and report novel de novo missense variants within the kinase domain of CDK13. Furthermore, we describe two nonsense variants and a recurrent frame-shift variant. We demonstrate the synthesis of two aberrant CDK13 transcripts in lymphoblastoid cells from an individual with a splice-site variant. Clinical characteristics of the individu...
Source: Clinical Genetics - February 2, 2018 Category: Genetics & Stem Cells Authors: van den Akker WMR, Brummelman I, Martis LM, Timmermans RN, Pfundt R, Kleefstra T, Willemsen MH, Gerkes EH, Herkert JC, van Essen AJ, Rump P, Vansenne F, Terhal PA, van Haelst MM, Cristian I, Turner CE, Cho MT, Begtrup A, Willaert R, Fassi E, van Gassen KL Tags: Clin Genet Source Type: research

Lack of clear and univocal genotype-phenotype correlation in Familial Mediterranean Fever patients: A systematic review.
Abstract Familial Mediterranean fever (FMF) is the most common autosomal recessive autoinflammatory disease. To date, following the isolation of more than 280 MEFV sequence variants, the genotype-phenotype correlation in FMF patients has been intensively investigated, however, an univocal and clear consensus has not been yet reached. Thus, the aim of this systematic review was to analyse the available literature findings in order to provide to scientific community an indirect estimation of the impact of genetic factors on the phenotypic variability of FMF. This systematic review has been conducted according to the...
Source: Clinical Genetics - February 2, 2018 Category: Genetics & Stem Cells Authors: Gangemi S, Manti S, Procopio V, Casciaro M, Di Salvo E, Cutrupi M, Ganci G, Salpietro C, Chimenz R, Cuppari C Tags: Clin Genet Source Type: research

Worldwide distribution of common IDUA pathogenic variants.
In conclusion, the most common pathogenic IDUA variant in MPS I patients are p.Trp402Ter, p.Gln70Ter and p.Pro533Arg. Knowledge about the genetic background of MPS I for each population is essential when developing new genotype-targeted therapies, as well as to enable faster genetic analysis and improve patient management. PMID: 29393969 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - February 2, 2018 Category: Genetics & Stem Cells Authors: Poletto E, Pasqualim G, Giugliani R, Matte U, Baldo G Tags: Clin Genet Source Type: research

Expanding the clinical and genetic spectra of NKX6-2-related disorder.
Abstract Hypomyelinating leukodystrophies (HLDs) affect the white matter of the central nervous system, and manifest as neurological disorders. They are genetically heterogeneous. Very recently, biallelic variants in NKX6-2 have been suggested to cause a novel form of autosomal recessive HLD. Using whole exome or whole genome sequencing, we identified the previously reported c.196delC and c.487C>G variants in NKX6-2 in three and two unrelated index cases, respectively; the novel c.608G>A variant was identified in a sixth patient. All variants were homozygous in affected family members only. Our patients shar...
Source: Clinical Genetics - February 1, 2018 Category: Genetics & Stem Cells Authors: Baldi C, Bertoli-Avella AM, Al-Sannaa N, Alfadhel M, Al-Thilhi K, Alameer S, Elmonairy AA, Al Shamsi AM, Abdelrahman HA, Al-Gazali L, Shawli A, Al Hakami F, Yavuz H, Kandaswamy KK, Rolfs A, Brandau O, Bauer P Tags: Clin Genet Source Type: research

Disclosure of Cardiac Variants of Uncertain Significance Results in an Exome Cohort.
This study examined the impact of disclosing sub-classifications of genetic variants of uncertain significance (VUS) on behavioral intentions. We studied return of VUS results to 79 individuals with a cardiomyopathy-associated VUS, sub-classified into VUS-high or VUS-low. Primary outcomes were perceived risk (absolute and comparative), perceived severity, perceived value of information, self-efficacy, decision regret, and behavioral intentions to share results and change behaviors. There was no significant difference between the two sub-classes in overall behavioral intentions (t=0.023, p=0.982) and each of the individual ...
Source: Clinical Genetics - January 31, 2018 Category: Genetics & Stem Cells Authors: Lawal TA, Lewis KL, Johnston JJ, Heidlebaugh AR, Ng D, Gaston-Johansson FG, Klein WMP, Biesecker BB, Biesecker LG Tags: Clin Genet Source Type: research

Three-dimensional genome architecture in health and disease.
Abstract More than a decade of massive DNA sequencing efforts has generated a large body of genomic, transcriptomic and epigenomic information that has provided a more and more detailed view of the functional elements and transactions within the human genome. Considerable efforts have also focused on linking these elements with one another by mapping their interactions and by establishing 3D genomic landscapes in various cell and tissue types. In parallel, multiple studies have associated genomic deletions, duplications and other rearrangements with human pathologies. In this review, we explore recent progresses t...
Source: Clinical Genetics - January 29, 2018 Category: Genetics & Stem Cells Authors: Ouimette JF, Rougeulle C, Veitia RA Tags: Clin Genet Source Type: research

Intellectual developmental disorder with cardiac arrhythmia syndrome in a child with compound heterozygous GNB5 variants.
Abstract Identification of a novel compound heterozygous of GNB5 in a patient with intellectual developmental disorder with cardiac arrhytmia (IDDCA), from non-consaguineous family. Three-dimensional modelling and in silico predictions suggest that GNB5 variants are causative of the phenotype, extending the number of IDDCA patients so far identified. PMID: 29368331 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - January 25, 2018 Category: Genetics & Stem Cells Authors: Vernon H, Cohen J, De Nittis P, Fatemi A, McClellan R, Goldstein A, Malerba N, Guex N, Reymond A, Merla G Tags: Clin Genet Source Type: research

Are all Xq26.2 duplications overlapping GPC3 on array-CGH a cause of Simpson-Golabi-Behmel syndrome? When do we need transcript analysis?
PMID: 29372559 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - January 25, 2018 Category: Genetics & Stem Cells Authors: Vuillaume ML, Moizard MP, Hammouche E, Delrue MA, Perrin L, Maftei C, Dupont C, Drunat S, Cottereau E, Baumann C, Toutain A Tags: Clin Genet Source Type: research