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Clinical Genetics

Piranit Nik Kantaputra, Bruce M Carlson
Split-hand/foot malformation (SHFM) are caused by mutations in TP63, DLX5, DLX6, FGF8, FGFR1, WNT10B, and BHLHA9. The clinical features of SHFM caused by mutations of these genes are not distinguishable. This implies that in normal situations these SHFM-associated genes share an underlying regulatory pathway that is involved in the development of the central parts of the hands and feet. The mutations in SHFM-related genes lead to dysregulation of Fgf8 in the central portion of the apical ectodermal ridge (AER) and subsequently lead to misexpression of a number of downstream target genes, failure of stratification of the AER, and thus SHFM...
August 12, 2018: Clinical Genetics
M-T Huynh, Y Chrétien, S Grison, J-L Delaunay, O Lascols, C T Tran, O Goria, M-J Ramond, V Barbu
No abstract text is available yet for this article.
August 9, 2018: Clinical Genetics
Nicolas Kalfa, Laura Gaspari, Margot Ollivier, Pascal Philibert, Anne Bergougnoux, Francoise Paris, Charles Sultan
During the last decade, a tremendous amount of work has been devoted to the study of the molecular genetics of isolated hypospadias and cryptorchidism, two minor forms of disorders of sex development (DSD). Beyond the genes involved in gonadal determination and sex differentiation, including those underlying androgen biosynthesis and signaling, new genes have been identified through genome wide association study and familial clustering. Even if no single genetic defect can explain the whole spectrum of DSD, these recent studies reinforce the strong role of the genetic background in the occurrence of these defects...
August 7, 2018: Clinical Genetics
Elena Repnikova, Jennifer Roberts, Alexander Kats, Sultan Habeebu, Caitlin Schwager, Julie Joyce, Michelle Manalang, Shivarajan Amudhavalli
Biparental/androgenetic mosaicism is a rarely diagnosed condition in humans. It is typically ascertained prenatally on the basis of placental mesenchymal dysplasia (PMD). Fetal outcome can range from demise due to intrauterine growth retardation to term delivery. Most of the published cases of liveborns represent females that are either completely normal or have features of Beckwith-Wiedemann syndrome (BWS). Only two healthy liveborn males with mosaicism detected in the placenta have been described to date...
August 7, 2018: Clinical Genetics
H Yavuz, A M Bertoli-Avella, M Alfadhel, N Al-Sannaa, K K Kandaswamy, W Al-Tuwaijri, A Rolfs, O Brandau, P Bauer
We identified the homozygous p.Arg12* variant in 5 patients with neurodevelopmental delay, but variation databases list many truncating heterozygous variants for this small 2-exon gene. As most of these affect the protein's C-terminus, loss-of-function mediated pathogenicity may be confined to bi-allelic truncating variants in exon 1 (nonsense-mediated decay!) or in the catalytically active Nudix box.
July 30, 2018: Clinical Genetics
Nisha Patel, Hisham Alkuraya, Shahad Sharaf Alzahrani, Sawsan R Nowilaty, Mohammed Zain Seidahmed, Amal Alhomedan, Tawfeg Ben-Omran, Nicola G Ghazi, Aida Al-Aqeel, Mohammed Al-Owain, Hamad I Alzaidan, Eissa Faqeih, Wesam Kurdi, Zuhair Rahbeeni, Niema Ibrahim, Firdous Abdulwahab, Mais Hashem, Ranad Shaheen, Mohamed Abouelhoda, Dorota Monies, Arif O Khan, Mohammed A Aldahmesh, Fowzan S Alkuraya
Retinal dystrophies (RD) are hereditary blinding eye conditions that are highly variable in their clinical presentation. The remarkable genetic heterogeneity that characterizes RD was a major challenge in establishing the molecular diagnosis in these patients until the recent advent of next-generation sequencing. It remains unclear, however, what percentage of autosomal recessive RD remain undiagnosed when all established RD genes are sequenced. We enrolled 75 families in which RD segregates in an apparently autosomal recessive manner...
July 28, 2018: Clinical Genetics
Kara Bellai-Dussault, Thi Tuyet Mai Nguyen, Nissan Vida Baratang, Daniel Alexander Jimenez Cruz, Philippe M Campeau
It is estimated that 0.5% of all mammalian proteins have a glycosylphosphatidylinositol (GPI)-anchor. GPI-anchored proteins play key roles, particularly in embryogenesis, neurogenesis, immune response and signal transduction. Due to their involvement in many pathways and developmental events, defects in the genes involved in their synthesis and processing can result in a variety of genetic disorders for which affected individuals display a wide spectrum of features. We compiled the clinical characteristics of 202 individuals with mutations in the GPI biosynthesis and processing pathway through a review of the literature...
July 27, 2018: Clinical Genetics
Eli B Cadoff, Ruth Sheffer, Shlomo Wientroub, Dror Ovadia, Vardiella Meiner, Jean E Schwarzbauer
Spondylometaphyseal dysplasia (SMD) is characterized by developmental changes in long bones and vertebrae. It has large phenotypic diversity and multiple genetic causes, including a recent link to novel variants in the extracellular matrix (ECM) protein fibronectin (FN), a regulator of ECM assembly and key link between the ECM and proper cell function. We identified a patient with a unique SMD, similar to SMD with corner fractures. The patient has been followed over 19 years and presents with short stature, genu varum, kyphoscoliosis, and pectus carinatum...
July 26, 2018: Clinical Genetics
Yuri Uchiyama, Kunio Yanagisawa, Shinji Kunishima, Masaaki Shiina, Yoshiyuki Ogawa, Mitsuko Nakashima, Junko Hirato, Eri Imagawa, Atsushi Fujita, Kohei Hamanaka, Satoko Miyatake, Satomi Mitsuhashi, Atsushi Takata, Noriko Miyake, Kazuhiro Ogata, Hiroshi Handa, Naomichi Matsumoto, Takeshi Mizuguchi
We report a patient with thrombocytopenia from a Japanese family with hemophilia A spanning four generations. Various etiologies of thrombocytopenia, including genetic, immunological, and hematopoietic abnormalities, determine the prognosis for this disease. In this study, we identified a novel heterozygous mutation in a gene encoding cytochrome c, somatic (CYCS, MIM123970) using whole exome sequencing. This variant (c.301_303del:p.Lys101del) is located in the α-helix of the cytochrome c (CYCS) C-terminal domain...
July 26, 2018: Clinical Genetics
Xingxing Lu, Qi Wang, Hongbo Gu, Xiao Zhang, Yu Qi, Yuhe Liu
Hearing loss is one of the most common sensory disorders worldwide, and about half of all occurrences are attributable to genetic factors. Here, we have identified a novel pathogenic variant in HOMER2 in a Chinese family with autosomal dominant, non-syndromic hearing loss. This is the second family reported globally with hearing loss caused by a variant in HOMER2. The pathogenic variant c.840_841insC in HOMER2 (NM_199330), segregating with the hearing-loss phenotype in the family, leads to a premature stop codon producing a truncated protein...
July 26, 2018: Clinical Genetics
Carla Lintas
There is growing evidence that epigenetic dysregulation plays a role in neurodevelopmental disorders. In humans, folate is one of the main donors of the methyl group required for the synthesis of S-adenosyl methionine which in turn is needed for DNA and histone methylation as key neurodevelopment processes. Folate deficiency during pregnancy has been correlated with neural tube defects and with a higher incidence of neurocognitive and/or neurobehavioral deficits. A similar outcome may be exerted by gene polymorphisms in folate or folate related pathways...
July 25, 2018: Clinical Genetics
H Flusser, D Halperin, R Kadir, Z Shorer, I Shelef, O S Birk
Four siblings of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of congenital microcephaly, facial dysmorphism, strabismus, developmental delay and ataxia with positive pyramidal signs. Toward the end of their first decade, they developed areflexia, multiple cranial neuropathies and severe polyneuropathy with progressive muscle weakness, affecting proximal and distal extremities. Physical assessment exhibited kyphoscoliosis, bilateral syndactyly and distal muscle wasting with drop-foot and pes cavus...
July 24, 2018: Clinical Genetics
N Rungroj, C Nettuwakul, N Sawasdee, S Sangnual, N Deejai, R A Misgar, A Pasena, S Khositseth, S Kirdpon, S Sritippayawan, S Vasuvattakul, P T Yenchitsomanus
Hereditary distal renal tubular acidosis (dRTA) is a rare genetic disease that is caused by mutations in SLC4A1, ATP6V1B1, or ATP6V0A4. However, there are many families with hereditary dRTA in whom the disease-causing genes are unknown. Accordingly, we performed whole exome sequencing and genetic studies of the members of a family with autosomal recessive dRTA of an unknown genetic etiology. Here, we report compound heterozygous pathogenic variations in tryptophan-aspartate repeat domain 72 (WDR72) (c.1777A>G [p...
July 20, 2018: Clinical Genetics
Petra Laššuthová, Katharina Vill, Sevim Erdem-Ozdamar, J Michael Schröder, Haluk Topaloglu, Rita Horvath, Wolfgang Müller-Felber, Boglarka Bansagi, Beate Schlotter-Weigel, Dieter Gläser, Jana Neupauerová, Lucie Sedláčková, David Staněk, Radim Mazanec, Joachim Weis, Pavel Seeman, Jan Senderek
Biallelic SBF2 mutations cause Charcot-Marie-Tooth disease type 4B2 (CMT4B2), a sensorimotor neuropathy with autosomal recessive inheritance and association with glaucoma. Since discovery of the gene mutation, only few additional patients have been reported. We identified seven CMT4B2 families with nine different SBF2 mutations. Revisiting genetic and clinical data from our cohort and the literature, SBF2 variants were private mutations, including exon-deletion and de novo variants. The neuropathy typically started in the first decade after normal early motor development, was predominantly motor and had a rather moderate course...
July 20, 2018: Clinical Genetics
Eri Imagawa, Edoarda V A Albuquerque, Bertrand Isidor, Satomi Mitsuhashi, Takeshi Mizuguchi, Satoko Miyatake, Atsushi Takata, Noriko Miyake, Margaret C S Boguszewski, César L Boguszewski, Antonio M Lerario, Mariana A Funari, Alexander A L Jorge, Naomichi Matsumoto
SUZ12 is a core component of polycomb repressive complex 2 (PRC2) along with EZH2 and EED. Recently, germline mutations in the SUZ12, EZH2 and EED genes have been reported in Weaver syndrome (WS) or Weaver-like syndrome, suggesting a functional link between PRC2 deficits and WS. However, only one case of a SUZ12 mutation presenting with Weaver-like syndrome has been reported. Here, we report a missense and a frameshift mutation in SUZ12 (c.1797A>C; p.Gln599His and c.844_845del; p.Ala282Glnfs*7), both of which are novel, in two individuals...
July 18, 2018: Clinical Genetics
Alice Lopes, Carla Rodrigues, Isabel Fonseca, Alexandra Sousa, Margarida Branco, Teresa Coelho, Jorge Sequeiros, Paula Freitas
Adult-onset, chronic, genetic diseases like transthyretin-related familial amyloid polyneuropathy Val30Met (TTR-FAP Val30Met), have a major psychosocial impact not only on patients, but also on families. Genetic risk may therefore be an increased factor in psychosocial impact of the disease on these families' functioning. To evaluate impact of genetic risk, a study was conducted to perceive the impact of the illness on families' functioning. Groups of TTR-FAP Val30Met patients, pre symptomatic carriers, partners and patients with multiple sclerosis (MS), a non-hereditary disease, were studied...
July 18, 2018: Clinical Genetics
A C Zielen, M J Khan, N Pollock, H Jiang, J Ahmed, R Nazli, M Jabeen, A Yatsenko, A Rajkovic
No abstract text is available yet for this article.
July 17, 2018: Clinical Genetics
Agnieszka Charzewska, Robert Maiwald, Kimia Kahrizi, Barbara Oehl-Jaschkowitz, Andreas Dufke, Johannes R Lemke, Herbert Enders, Hossein Najmabadi, Andreas Tzschach, Wiebke Hachmann, Corinna Menzel, Melanie Bienek, Jarosław Poznański, Magdalena Nawara, Tatiana Chilarska, Ewa Obersztyn, Dorota Hoffman-Zacharska, Monika Gos, Jerzy Bal, Vera M Kalscheuer
MED12 is a member of the large Mediator complex that controls cell growth, development, and differentiation. Mutations in MED12 disrupt neuronal gene expression and lead to at least three distinct X-linked intellectual disability (XLID) syndromes (FG, Lujan-Fryns, and Ohdo). Here we describe six families with missense variants in MED12 (p.(Arg815Gln), p.(Val954Gly), p.(Glu1091Lys), p.(Arg1295Cys), p.(Pro1371Ser) and p.(Arg1148His), the latter being firstly reported in affected females) associated with a continuum of symptoms rather than distinct syndromes...
July 13, 2018: Clinical Genetics
K A Myers, D L Johnstone, D A Dyment
The rapid pace of disease gene discovery has resulted in tremendous advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, and genomes are now available and have led to higher diagnostic rates and insights into the underlying disease processes. As such, the contribution to the care of patients by medical geneticists, neurogeneticists and genetic counselors are significant; the dysmorphic examination, the necessary pre- and post-test counseling, the selection of the appropriate next-generation sequencing-based test(s), and the interpretation of sequencing results require a care provider to have a comprehensive working knowledge of the strengths and limitations of the available testing technologies...
July 10, 2018: Clinical Genetics
A Moirangthem, D L Narayanan, P Jacob, G Nishimura, G Mortier, K M Girisha
We report a boy with Eiken syndrome caused by a homozygous missense variant in Parathyroid hormone 1 receptor (PTH1R) c.103G > A [p.(Glu35Lys)]. Eiken syndrome is a very rare skeletal dysplasia due to bi-allelic variants in PTH1R. Only one affected family has been known to-date. The hallmarks include delayed ossification of bone including the epiphyses, pubic symphysis, and primary ossification centers of the short tubular bones, coarse bone trabeculae, and modeling abnormalities. The phenotype being described here recapitulates the delayed ossification and modeling abnormalities of Eiken syndrome...
July 10, 2018: Clinical Genetics
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