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Clinical Genetics

Kimia Kahrizi, Hao Hu, Masoumeh Hosseini, Vera M Kalscheuer, Zohreh Fattahi, Maryam Beheshtian, Vanessa Suckow, Marzieh Mohseni, Bettina Lipkowitz, Sepideh Mehvari, Zohreh Mehrjoo, Tara Akhtarkhavari, Zhila Ghaderi, Maryam Rahimi, Sanaz Arzhangi, Payman Jamali, Milad Falahat Chian, Pooneh Nikuei, Farahnaz Sabbagh Kermani, Farnaz Sadeghinia, Roshanak Jazayeri, Seyed Hassan Tonekaboni, Atefeh Khoshaeen, Haleh Habibi, Fatemeh Pourfatemi, Faezeh Mojahedi, Mohammad-Reza Khodaie-Ardakani, Reza Najafipour, Thomas F Wienker, Hossein Najmabadi, Hans-Hilger Ropers
In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. Due to the high rate of parental consanguinity which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in Near- and Middle-East countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but due to the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown...
October 12, 2018: Clinical Genetics
Luigi Boccuto, Ludovico Abenavoli, Lauren Cascio, Sujata Srikanth, Barbara DuPont, Andrew R Mitz, Roger Curtis Rogers, Katy Phelan
The PNPLA3 gene maps in the 22q13 region and can have modifying effects on the phenotype of patients with Phelan-McDermid syndrome (PMS). The PNPLA3 p.I148M variant was detected in two PMS patients presenting with refractory seizures, gastrointestinal issues, and liver dysfunction. The p.I148M variant leads to macrovescicular steaosis and predisposes to liver disorders from steatohepatitis to fibrosis. Accumulation of lipid macrovescicles in the hepatocytes affects several pathways, including the metabolismof anti-epileptics, possibly leading to the lack of response to anti-epileptic treatments reported in the two cases...
October 11, 2018: Clinical Genetics
Hanadi A Abdelrahman, Aisha M Al-Shamsi, Bassam R Ali, Lihadh Al-Gazali
No abstract text is available yet for this article.
October 11, 2018: Clinical Genetics
Matthias Baumann, Herbert Schreiber, Beate Schlotter-Weigel, Wolfgang N Löscher, Rolf Stucka, Daniela Karall, Tim M Strom, Peter Bauer, Birgit Krabichler, Christine Fauth, Dieter Glaeser, Jan Senderek
MPV17 encodes a putative channel-forming protein of the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis. MPV17 mutations were first reported in patients with Navajo neurohepatopathy, an autosomal recessive mitochondrial DNA depletion syndrome, characterized by early-onset liver failure, failure to thrive as well as central and peripheral neurological involvement. Recently, two patients with juvenile-onset peripheral sensorimotor neuropathy associated with an MVP17 c...
October 9, 2018: Clinical Genetics
Yan-Wei Sha, Xiong Wang, Xiaohui Xu, Lu Ding, Wen-Sheng Liu, Ping Li, Zhi-Ying Su, Jing Chen, Li-Bin Mei, Liang-Kai Zheng, Hai-Long Wang, Shuang-Bo Kong, Min You, Jian-Feng Wu
The majority of men with defects in spermatogenesis remain undiagnosed. Acephalic spermatozoa is one of the diseases causing primary infertility. However, the causes underlying over half of affected cases remain unclear. Here, we report by whole-exome sequencing the identification of homozygous and compound heterozygous truncating mutations in PMFBP1 of two unrelated individuals with acephalic spermatozoa. PMFBP1 was highly and specifically expressed in human and mouse testis. Further, immunofluorescence staining in sperm from a normal control showed that PMFBP1 localizes to the head-flagella junction region, and the absence of PMFBP1 was confirmed in patients harboring PMFBP1 mutations...
October 8, 2018: Clinical Genetics
Justine Lerat, Crystel Bonnet, François Cartault, Natalie Loundon, Marie-Line Jacquemont, Françoise Darcel, Isabelle Rouillon, Kheira Mezouaghi, Agnes Guichet, Julie Litzler, Roselyne Gesny, Souad Gherbi, Ines B E N Aissa, Fabienne S A I N T J A M E S Digeon, Eréa-Nöel Garabedian, Jean-Paul Bonnefont, Emmanuelle Genin, Françoise Denoyelle, Laurence Jonard, Sandrine Marlin
Reunion Island is a French oversea department in the Indian Ocean with 1.6/1000, an estimated prevalence of deafness that is almost double as compared to the mainland France. Twelve children having isolated bilateral prelingual profound deafness along with motor delay attributed to vestibular areflexia were enrolled. Their mean walking age was 19 months. Electroretinography and temporal bone CT-scans were normal in all cases. A novel homozygous frameshift LHFPL5 variant c.185delT p.(Phe62Serfs*23) was identified using Whole Exome Sequencing (WES)...
October 8, 2018: Clinical Genetics
Nathalia Lisboa Gomes, Leila Cristina Pedroso de Paula, Juliana Moreira Silva, Thatiana Evilen Silva, Antônio Marcondes Lerário, Mirian Y Nishi, Rafael Loch Batista, José Antônio Júnior, Daniela Moraes, Elaine M F Costa, Tatiana Prade Hemesath, Guilherme Guaragna, Júlio César Loguercio Leite, Clarissa Gutierrez Carvalho, Sorahia Domenice, Eduardo Corrêa Costa, Berenice B Mendonca
Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor-1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) due to gonadal dysgenesis. We report a novel frameshift WT1 variant identified in a SRY-negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD-related genes identified a novel heterozygous WT1 c...
October 7, 2018: Clinical Genetics
Mattia Gentile, Emanuele Agolini, Dario Cocciadiferro, Romina Ficarella, Emanuela Ponzi, Emanuele Bellacchio, Maria Fatima Antonucci, Antonio Novelli
Biallelic Exostin-2 (EXT2) pathogenic variants have been described as the cause of the Seizures-Scoliosis-Macrocephaly (SSM) syndrome (OMIM 616682) characterized by intellectual disability, facial dysmorphisms and seizures. More recently it has been proposed to rename this disorder with the acronym AREXT2 (autosomal recessive EXT2-related syndrome). Here we report the third family affected by AREXT2 syndrome, harbouring compound missense variants in EXT2, p.Asp227Asn, and p.Tyr608Cys. In addition, our patients developed multiple exostoses, which were not observed in the previously described families...
October 4, 2018: Clinical Genetics
Julian C Lui, Youn Hee Jee, Audrey Lee, Shanna Yue, Jacob Wagner, Deirdre E Donnelly, Karen S Vogt, Jeffrey Baron
In many children with short stature, the etiology of the decreased linear growth remains unknown. We sought to identify the underlying genetic etiology in a patient with short stature, irregular growth plates of the proximal phalanges, developmental delay, and mildly dysmorphic facial features. Exome sequencing identified a de novo, heterozygous, nonsense mutation (c.1606C> T:p.R536X) in QRICH1. In vitro studies confirmed that the mutation impaired expression of the QRICH1 protein. siRNA-mediated knockdown of Qrich1 in primary mouse epiphyseal chondrocytes caused downregulation of gene expression associated with hypertrophic differentiation...
October 3, 2018: Clinical Genetics
Rosettia Ho, Robert A Hegele
The nuclear lamins are important members of the intermediate filament family of proteins, involved in structural support and regulation of the nuclear lamina. Different mutations in various members of these type V intermediate filament proteins produce a staggering range of human disease phenotypes, which collectively have been termed 'laminopathies'. Compelling examples are the wide range of inherited disorders that result from rare variants in LMNA encoding lamin A/C. These laminopathies include skeletal and cardiac muscle disorders, neuropathies, multi-system progeroid disorders, and lipodystrophies, of which the latter is associated with several metabolic complications...
October 3, 2018: Clinical Genetics
Naomi Tsuchida, Keisuke Hamada, Masaaki Shiina, Mitsuhiro Kato, Yu Kobayashi, Jun Tohyama, Kazue Kimura, Kyoko Hoshino, Vigneswari Ganesan, Keng Wee Teik, Mitsuko Nakashima, Satomi Mitsuhashi, Takeshi Mizuguchi, Atsushi Takata, Noriko Miyake, Hirotomo Saitsu, Kazuhiro Ogata, Satoko Miyatake, Naomichi Matsumoto
N-methyl-D-aspartate (NMDA) receptors are glutamate-activated ion channels that are widely distributed in the central nervous system and essential for brain development and function. Dysfunction of NMDA receptors has been associated with various neurodevelopmental disorders. Recently, a de novo recurrent GRIN2D missense variant was found in two unrelated patients with developmental and epileptic encephalopathy. In this study, we identified by whole exome sequencing novel heterozygous GRIN2D missense variants in three unrelated patients with severe developmental delay and intractable epilepsy...
October 3, 2018: Clinical Genetics
Cécile Méjécase, Aurélie Hummel, Saddek Mohand-Saïd, Camille Andrieu, Said El Shamieh, Aline Antonio, Christel Condroyer, Fiona Boyard, Marine Foussard, Steven Blanchard, Mélanie Letexier, Jean-Paul Saraiva, José-Alain Sahel, Christina Zeitz, Isabelle Audo
Genetic investigations were performed in three brothers from a consanguineous union, the two oldest diagnosed with rod-cone dystrophy (RCD), the youngest with early-onset cone-rod dystrophy and the two youngest with nephrotic-range proteinuria. Targeted next-generation sequencing did not identify homozygous pathogenic variant in the oldest brother. Whole exome sequencing (WES) applied to the family identified compound heterozygous variants in CC2D2A (c.2774G>C p.(Arg925Pro); c.4730_4731delinsTGTATA p.(Ala1577Valfs*5)) in the three brothers with a homozygous deletion in CNGA3 (c...
September 29, 2018: Clinical Genetics
Florentia Fostira, Emmanouil Kontopodis, Paraskevi Apostolou, Maria Fragkaki, Nikolaos Androulakis, Drakoulis Yannoukakos, Irene Konstantopoulou, Emmanouil Saloustros
No abstract text is available yet for this article.
September 24, 2018: Clinical Genetics
Krzysztof Szczałuba, Joanna J Chmielewska, Olga Sokolowska, Małgorzata Rydzanicz, Krystyna Szymańska, Wojciech Feleszko, Paweł Włodarski, Anna Biernacka, Victor Murcia Pienkowski, Anna Walczak, Elżbieta Bargeł, Katarzyna Królewczyk, Agata Nowacka, Piotr Stawiński, Dominika Nowis, Magdalena Dziembowska, Rafał Płoski
Protein tyrosine phosphatase non-receptor type 4 (PTPN4) encodes non-receptor protein tyrosine phosphatase implicated in synaptic plasticity and innate immune response. The only report of PTPN4-associated disease described a neurodevelopmental disorder associated with a whole gene deletion. We describe a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems with a novel mosaic de novo variant in PTPN4 (hg19 chr2:g.120620188 T > C, NM_002830.3:p...
September 21, 2018: Clinical Genetics
Malin Kvarnung, Fulya Taylan, Daniel Nilsson, Britt-Marie Anderlid, Helena Malmgren, Kristina Lagerstedt-Robinson, Eva Holmberg, Magnus Burstedt, Magnus Nordenskjöld, Ann Nordgren, Elisabeth Syk Lundberg
We have investigated 20 consanguineous families with multiple children affected by rare disorders. Detailed clinical examinations, exome sequencing of affected as well as unaffected family members and further validation of likely pathogenic variants were performed. In 16/20 families, we identified pathogenic variants in autosomal recessive disease genes (ALMS1, PIGT, FLVCR2, TFG, CYP7B1, ALG14, EXOSC3, MEGF10, ASAH1, WDR62, ASPM, PNPO, ERCC5, KIAA1109, RIPK4, MAN1B1). A number of these genes have only rarely been reported previously and our findings thus confirm them as disease genes, further delineate the associated phenotypes and expand the mutation spectrum with reports of novel variants...
September 16, 2018: Clinical Genetics
Graciane Petre, Patrick Lorès, Hervé Sartelet, Aurélie Truffot, Brice Poreau, Sandrine Brandeis, Guillaume Martinez, Véronique Satre, Radu Harbuz, Pierre F Ray, Florence Amblard, Françoise Devillard, Gaëlle Vieville, Francois Berger, Pierre-Simon Jouk, Daniel Vaiman, Aminata Touré, Charles Coutton, Marie Bidart
We report findings from a male fetus of 26 weeks' gestational age with severe isolated intrauterine growth restriction (IUGR). Chromosomal microarray analysis (CMA) on amniotic fluid cells revealed a 1.06-Mb duplication in 19q13.42 inherited from the healthy father. This duplication contains 34 genes including ZNF331, a gene encoding a zinc-finger protein specifically imprinted (paternally expressed) in the placenta. Study of the ZNF331 promoter by methylation-specific-multiplex ligation-dependent probe amplification (MS-MLPA) showed that the duplicated allele was not methylated in the fetus unlike in the father's genome, suggesting both copies of the ZNF331 gene are expressed in the fetus...
September 16, 2018: Clinical Genetics
Eveline Kersten, Maartje J Geerlings, Marc Pauper, Jordi Corominas, Bjorn Bakker, Lebriz Altay, Sascha Fauser, Eiko K de Jong, Carel B Hoyng, Anneke I Hollander
It can be clinically challenging to distinguish dry age-related macular degeneration (AMD) from AMD-mimicking dystrophies, and sometimes misdiagnosis occurs. With upcoming therapies for dry AMD it is important to exclude patients with a different retinal disease from clinical trials. In this study we evaluated the occurrence of AMD-mimicking dystrophies in an AMD cohort. Whole-exome sequencing (WES) was performed in 218 patients with intermediate AMD or geographic atrophy secondary to AMD and 133 control individuals...
September 14, 2018: Clinical Genetics
Karlien Mul, Nicol C Voermans, Richard J L F Lemmers, Marianne A Jonker, Patrick J van der Vliet, George W Padberg, Baziel G M van Engelen, Silvère M van der Maarel, Corinne G C Horlings
To determine how much of the clinical variability in facioscapulohumeral muscular dystrophy type 1 can be explained by the D4Z4 repeat array size, D4Z4 methylation and familial factors, we included 152 carriers of an FSHD1 allele (23 single cases, 129 familial cases from 37 families) and performed state-of-the-art genetic testing, extensive clinical evaluation and quantitative muscle MRI. Familial factors accounted for 50% of the variance in disease severity (FSHD clinical score). The explained variance by the D4Z4 repeat array size for disease severity was limited (approximately 10%), and varied per body region (facial muscles, upper and lower extremities approximately 30%, 15% and 3%, respectively)...
September 13, 2018: Clinical Genetics
Shoji Yano, Atsuko Fujimoto, Jeanne Morin-Leisk, Naomichi Matumoto, Noriko Miyake, Meghan Gillespie, Harry Gao
No abstract text is available yet for this article.
September 12, 2018: Clinical Genetics
U S Melo, F Freua, D S Lynch, B D Ripa, R B Tenorio, J A M Saute, F de Souza Leite, J Kitajima, H Houlden, M Zatz, F Kok
No abstract text is available yet for this article.
September 10, 2018: Clinical Genetics
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