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Clinical Genetics

G Gillessen-Kaesbach, B Albrecht, T Eggermann, M Elbracht, D Mitter, S Morlot, C M A van Ravenswaaij-Arts, S Schulz, G Strobl-Wildemann, K Buiting, J Beygo
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 with an imprinting defect in a mosaic state as well as one complete and one segmental maternal uniparental disomy of chromosome 14...
February 22, 2018: Clinical Genetics
M Sébastien, B Ange-Line, A Mirna, C Martin, S Elisabeth, G Cyril, G Anne-Marie, C Aude, C Perrine, H Delphine, F Anne, H Nada, V Antonio, T-M-T Frédéric, P Christophe, D Yannis, T-R Christel, F Laurence
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...
February 20, 2018: Clinical Genetics
F Fattori, C Fiorillo, C Rodolico, G Tasca, M Verardo, E Bellacchio, S Pizzi, A Ciolfi, G Fagiolari, A Lupica, P Broda, M Pedemonte, M Moggio, C Bruno, M Tartaglia, E Bertini, A D'Amico
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-/- knockout mouse model...
February 19, 2018: Clinical Genetics
A-L Bruel, J Levy, N Elenga, A Defo, A Favre, H Lucron, Y Capri, L Perrin, S Passemard, Y Vial, A-C Tabet, L Faivre, C Thauvin-Robinet, A Verloes
Oral-facial-digital (OFD) syndromes are a subgroup of ciliopathies distinguished by the co-occurrence of hamartomas and/or multiple frenula of the oral region and digital anomalies. Several clinical forms of OFD are distinguished by their associated anomalies and/or inheritance patterns, and at least 20 genetic types of OFD have been delineated. We describe here a child with preaxial and postaxial polydactyly, lingual hamartoma, a congenital heart defect, delayed development and cerebellar peduncles displaying the molar tooth sign...
February 16, 2018: Clinical Genetics
N Patel, A O Khan, S Alsahli, G Abdel-Salam, S R Nowilaty, A M Mansour, A Nabil, M Al-Owain, S Sogati, M A Salih, A M Kamal, H Alsharif, H Alsaif, S S Alzahrani, F Abdulwahab, N Ibrahim, M Hashem, T Faquih, Z A Shah, M Abouelhoda, D Monies, M Dasouki, R Shaheen, S Majid, M A Aldahmesh, F S Alkuraya
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 molecular karyotyping...
February 16, 2018: Clinical Genetics
A Ben-Mahmoud, S Ben-Salem, M Al-Sorkhy, A John, B R Ali, L Al-Gazali
Al-Gazali syndrome encompasses several clinical features including prenatal growth retardation, large joints contractures with camptodactyly, bilateral talipes equinovarus, small mouth, anterior segment anomalies of the eyes, and early lethality. Recently, a baby with features very similar to Al-Gazali syndrome was found to have compound heterozygous variants in B3GALT6. This gene encodes Beta-1,3-galactosyltransferase 6 (β3GalT6), an essential component of the glycosaminoglycan synthesis pathway. Pathogenic variants in B3GALT6 have also been shown to cause Ehlers-Danlos syndrome spondylodysplastic type (spEDS-B3GALT6) and spondylo-epimetaphyseal dysplasia with joint laxity type I (SEMD-JL1)...
February 14, 2018: Clinical Genetics
M M Rangel-Sosa, L E Figuera-Villanueva, I A González-Ramos, Y X Pérez-Páramo, L A Martínez-Jacobo, L Arnaud-López, J A Nastasi-Catanese, A M Rivas-Estilla, K A Galán-Huerta, A Rojas-Martínez, R Ortiz-López, C Córdova-Fletes
Splicing-related gene mutations might affect the expression of a single gene or multiple genes and cause clinically heterogeneous diseases. With the advent of next-generation sequencing, several splicing gene mutations have been exposed, yet most major spliceosome genes have no reports of germline mutations and therefore, their effects are largely unknown. 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...
February 13, 2018: Clinical Genetics
C Avgerinou, F Fostira, P Economopoulou, A Psyrri
Synchronous loss-of-function mutations in the cancer predisposing genes, PTEN and PALB2 identified by multigene panel.
February 11, 2018: Clinical Genetics
M L Dentici, A Terracciano, E Bellacchio, R Capolino, A Novelli, M C Digilio, B Dallapiccola
Circumferential skin creases Kunze type (CSC-KT; OMIM 156610, 616734) is a rare disorder characterized by folding of excess skin, which leads to ringed creases, known as Michelin Tyre Baby Syndrome (MTBS). CSC-KT patients also exhibit facial dysmorphism, growth retardation, intellectual disability (ID) and multiple congenital malformation. Recently, two heterozygous mutations in TUBB gene and four mutations (both homozygous and heterozygous) in MAPRE2 gene were identified in 3 and 4 CSC-KT patients, respectively...
February 10, 2018: Clinical Genetics
S A Shalev
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...
February 10, 2018: Clinical Genetics
Y Fan, A Liu, C Wei, H Yang, X Chang, S Wang, Y Yuan, C Bonnemann, Q Wu, X Wu, H Xiong
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...
February 8, 2018: Clinical Genetics
I Michałus, A Rusińska
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...
February 8, 2018: Clinical Genetics
D Monies, J Anabrees, N Ibrahim, H Elbardisy, M Abouelhoda, B F Meyer, F S Alkuraya
No abstract text is available yet for this article.
February 8, 2018: Clinical Genetics
E A Faqeih, M Almannai, M M Saleh, A H AlWadie, M M Samman, F S Alkuraya
The association between KCTD3 gene and neurogenetic disorders has only been published recently. 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 myelination...
February 6, 2018: Clinical Genetics
G A Yanus, T A Akhapkina, A O Ivantsov, E V Preobrazhenskaya, S N Aleksakhina, I V Bizin, A P Sokolenko, N V Mitiushkina, E S Kuligina, E N Suspitsin, A R Venina, M M Holmatov, O A Zaitseva, O S Yatsuk, D V Pashkov, A M Belyaev, A V Togo, E N Imyanitov, A G Iyevleva
Distribution of cancer-predisposing mutations demonstrates significant interethnic variations. This study aimed to evaluate patterns of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. APC gene defects were identified in 26/38 (68%) subjects with colon polyposis; 8/26 (31%) APC mutations were associated with two known mutational hotspots (p.E1309Dfs*4 (n = 5) and p.Q1062fs* (n = 3)), while 6/26 (23%) mutations were novel (p.K73Nfs*6, p.S254Hfs*12, p.S1072Kfs*9, p.E1547Kfs*11, p...
February 6, 2018: Clinical Genetics
A Angius, S Cossu, P Uva, M Oppo, S Onano, I Persico, G Fotia, R Atzeni, G Cuccuru, M Asunis, F Cucca, D Pruna, L Crisponi
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 disturbance, hyperkinetic movement disorder, cachexia and chronic constipation...
February 5, 2018: Clinical Genetics
W Shen, B A Young, M Bosworth, K E Wright, A N Lamb, Y Ji
No abstract text is available yet for this article.
February 5, 2018: Clinical Genetics
Li Ou, Michael J Przybilla, Chester B Whitley
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...
February 2, 2018: Clinical Genetics
E Poletto, G Pasqualim, R Giugliani, U Matte, G Baldo
Mucopolysaccharidosis type I (MPS I) is a rare disorder caused by deleterious sequence variants in the α-L-iduronidase (IDUA) gene. More than 200 pathogenic variants have been described so far, but their frequencies have not yet been analysed on a worldwide scale. To address this, we analysed the genotypes of MPS I patients from thirty-five published studies papers. The most common pathogenic variant observed was p.Trp402Ter. With frequencies of up to 63%, it was the major allele in most European countries, America and Australia...
February 2, 2018: Clinical Genetics
Sebastiano Gangemi, Sara Manti, Vincenzo Procopio, Marco Casciaro, Eleonora Di Salvo, Mariaconcetta Cutrupi, Gloria Ganci, Carmelo Salpietro, Roberto Chimenz, Caterina Cuppari
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...
February 2, 2018: Clinical Genetics
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