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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

Integrated Analysis of SNP, CNV and Gene Expression Data in Genetic Association Studies.
We present different methods to compare this gene list with the other three possible lists that result from the combinations of the following pairs of data: SNP genotype with gene expression, CNV genotype with gene expression, and SNP genotype with CNV genotype. The comparison is done using three different cancer datasets and two different methods of comparison. Our results show that integrating SNP, CNV, and gene expression data give better association results than integrating any pair of three data. PMID: 28685831 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - July 7, 2017 Category: Genetics & Stem Cells Authors: Momtaz R, Ghanem NM, El-Makky NM, Ismail MA Tags: Clin Genet Source Type: research

Genetic characterization of GSD I in Serbian population revealed unexpectedly high incidence of GSD Ib and three novel SLC37A4 variants.
Abstract Glycogen storage disease (GSD) type I is inborn metabolic disease characterized by accumulation of glycogen in multiple organs. We analyzed 38 patients with clinical suspicion of GSD I using Sanger and next-generation sequencing (NGS). We identified 28 GSD Ib and five Ia patients. In five patients, GSD III, VI, IX, cholesteryl-ester storage disease and Shwachman-Diamond syndrome diagnoses were set using NGS. Incidences for GSD Ia and GSD Ib were estimated at 1:172746 and 1:60461 live-births respectively. Two variants were identified in G6PC gene: c.247C>T (p.Arg83Cys) and c.518T>C (p.Leu173Pro). In ...
Source: Clinical Genetics - July 7, 2017 Category: Genetics & Stem Cells Authors: Skakic A, Djordjevic M, Sarajlija A, Klaassen K, Tosic N, Kecman B, Ugrin M, Spasovski V, Pavlovic S, Stojiljkovic M Tags: Clin Genet Source Type: research

Mining for mitochondrial mechanisms: linking known syndromes to mitochondrial function.
Abstract Mitochondrial disorders (MDs) are caused by defects in one or multiple complexes of the oxidative phosphorylation (OXPHOS) machinery. MDs are associated with a broad range of clinical signs and symptoms, and have considerable clinical overlap with other neuromuscular syndromes. This overlap might be due to involvement of mitochondrial pathways in some of these non-mitochondrial syndromes. Here, we give an overview of around 25 non-mitochondrial syndromes, diagnosed in patients who were initially suspected to have a MD on the basis of clinical and biochemical parameters. In addition, we highlight the mitoc...
Source: Clinical Genetics - July 7, 2017 Category: Genetics & Stem Cells Authors: Panneman DM, Smeitink JA, Rodenburg RJ Tags: Clin Genet Source Type: research

NDUFA9 point mutations cause a variable mitochondrial complex I assembly defect.
ns LG Abstract Mitochondrial respiratory chain complex I consists of 44 different subunits and contains three functional modules: the Q-, the N- and the P-module. NDUFA9 is a Q-module subunit required for complex I assembly or stability. However, its role in complex I biogenesis has not been studied in patient fibroblasts. So far, a single patient carrying an NDUFA9 variant with a severe neonatally fatal phenotype has been reported. Via exome sequencing, we identified a novel homozygous NDUFA9 missense variant in another patient with a milder phenotype including childhood-onset progressive generalized dystonia and...
Source: Clinical Genetics - July 3, 2017 Category: Genetics & Stem Cells Authors: Baertling F, Sánchez-Caballero L, van den Brand MA, Fung CW, Chan SH, Wong VC, Hellebrekers DME, de Coo IFM, Smeitink JA, Rodenburg RJ, Nijtmans LG Tags: Clin Genet Source Type: research

Protein misfolding diseases: prospects of pharmacological treatment.
erdá C, Pérez B Abstract Protein misfolding has been linked to numerous inherited diseases. Loss- and gain-of-function mutations (common features of genetic diseases) may cause the destabilization of proteins, leading to alterations in their properties and/or cellular location, resulting in their incorrect functioning. Misfolded proteins can, however, be rescued via the use of proteostasis regulators and/or pharmacological chaperones, suggesting that treatments with small molecules might be developed for a range of genetic diseases. This work describes the potential of these small molecules in this r...
Source: Clinical Genetics - July 3, 2017 Category: Genetics & Stem Cells Authors: Gámez A, Yuste-Checa P, Brasil S, Briso-Montiano Á, Desviat LR, Ugarte M, Pérez-Cerdá C, Pérez B Tags: Clin Genet Source Type: research

Phenotypic spectrum of mutations in IBA57, a candidate gene for cavitating leukoencephalopathy.
This study provided more information about the natural history and evolution of neuroimaging. Combined with previously reported patient studies, our findings suggest that defects in IBA57 can produce diverse phenotypes. IBA57 should be considered a candidate gene for cavitating leukoencephalopathy. PMID: 28671726 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - July 3, 2017 Category: Genetics & Stem Cells Authors: Liu M, Zhang J, Zhang Z, Zhou L, Jiang Y, Wang J, Xiao J, Wu Y Tags: Clin Genet Source Type: research

Next generation phenotyping in Emanuel and Pallister Killian Syndrome using computer-aided facial dysmorphology analysis of 2D photos.
Abstract High throughput approaches are continuously progressing and have become a major part of clinical diagnostics. Still, the critical process of detailed phenotyping and gathering clinical information has not changed much in the last decades. Forms of Next Generation Phenotyping (NGP) are needed to increase further the value of any kind of genetic approaches, including timely considering of (molecular) cytogenetics during the diagnostic quest. As NGP we used in this study the Facial Dysmorphology Novel Analysis (FDNA) technology to automatically identify facial phenotypes associated with Emanuel (ES) and Pall...
Source: Clinical Genetics - June 29, 2017 Category: Genetics & Stem Cells Authors: Liehr T, Acquarola N, Pyle K, St-Pierre S, Rinholm M, Bar O, Wilhelm K, Schreyer I Tags: Clin Genet Source Type: research

A homozygous I684T in GLE1 as a novel cause of arthrogryposis and motor neuron loss.
Abstract Mutations in GLE1, RNA export mediator (GLE1) gene have previously been shown to cause motor neuron diseases such as Lethal congenital contracture syndrome 1 (LCCS1) and Lethal arthrogryposis with anterior horn cell disease (LAAHD), including arthrogryposis, fetal akinesis and motor neuron loss as common clinical features. The homozygous FinMajor mutation p.T144_E145insPFQ has been described as one of the causes for LCCS1 whereas LAAHD is caused by a heterocompound FinMajor mutation together with p.R569H, p.V617M or p.I684T missense mutation. None of these heterocompound missense mutations have previously...
Source: Clinical Genetics - June 28, 2017 Category: Genetics & Stem Cells Authors: Paakkola T, Vuopala K, Kokkonen H, Ignatius J, Valkama M, Moilanen JS, Fahiminiya S, Majewski J, Hinttala R, Uusimaa J Tags: Clin Genet Source Type: research

A 37-years-old Menkes disease patient - Residual ATP7A activity and early copper administration as key factors in beneficial treatment.
h;ller LB Abstract Menkes disease is a lethal disorder characterized by severe neurological symptoms and connective tissue abnormalities; and results from malfunctioning of cuproenzymes, which cannot receive copper due to a defective intracellular copper transporting protein, ATP7A. Early parenteral copper-histidine supplementation may modify disease progression substantially but beneficial effects of long-term treatment have been recorded in only a few patients. Here we report on the eldest surviving Menkes disease patient (37 years) receiving early-onset and long-term copper treatment. He has few neurolog...
Source: Clinical Genetics - June 28, 2017 Category: Genetics & Stem Cells Authors: Tümer Z, Petris M, Zhu S, Mercer J, Bukrinski J, Bilz S, Baerlocher K, Horn N, Møller LB Tags: Clin Genet Source Type: research

A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency.
This report provides evidence that bi-allelic null PAX1 mutations may lead to a multi-system autosomal recessive disorders, where severe combined immunodeficiency might represent the main feature. PMID: 28657137 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - June 28, 2017 Category: Genetics & Stem Cells Authors: Paganini I, Sestini R, Capone GL, Putignano AL, Contini E, Giotti I, Gensini F, Marozza A, Barilaro A, Porfirio B, Papi L Tags: Clin Genet Source Type: research

Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I.
Haack TB Abstract Biallelic mutations in SLC25A46, encoding a modified solute transporter involved in mitochondrial dynamics, have been identified in a wide range of conditions such as hereditary motor and sensory neuropathy with optic atrophy type VIB (OMIM: *610826) and congenital lethal pontocerebellar hypoplasia (PCH). To date, 18 patients from 13 families have been reported, presenting with the key clinical features of optic atrophy, peripheral neuropathy, and cerebellar atrophy. The course of the disease was highly variable ranging from severe muscular hypotonia at birth and early death to first manifestati...
Source: Clinical Genetics - June 27, 2017 Category: Genetics & Stem Cells Authors: Braunisch MC, Gallwitz H, Abicht A, Diebold I, Holinski-Feder E, Van Maldergem L, Lammens M, Kovács-Nagy R, Alhaddad B, Strom TM, Meitinger T, Senderek J, Rudnik-Schöneborn S, Haack TB Tags: Clin Genet Source Type: research

Functional Analysis of p.Ala253_Leu254insAsn Mutation in PLS3 Responsible for X-linked Osteoporosis.
Abstract Mutations in Plastin-3 (PLS3) have been identified as a cause of X-linked osteoporosis. To reveal the molecular mechanism of PLS3 on osteoporosis, we characterized the p.Ala253_Leu254insAsn mutation in PLS3. We first identified Lymphocyte cytosolic protein 1 (LCP1) as a binding partner of PLS3 and the mutation disrupted the interaction between them. We then confirmed the roles of PLS3 and LCP1 in the regulation of intracellular Ca(2+) , which was weakened by the mutant PLS3. Moreover, the interaction between PLS3 and LCP1 was enhanced under a low concentration of extracellular Ca(2+) . However, the mutati...
Source: Clinical Genetics - June 24, 2017 Category: Genetics & Stem Cells Authors: Wang L, Zhai Q, Zhao P, Xiang X, Zhang X, Tian W, Li T Tags: Clin Genet Source Type: research

Spectrum of mutations in cystinuria patients presenting with prenatal hyperechoic colon.
This study shows a relationship between genotype and the clinical form of cystinuria, suggesting that only the patients with the most severe mutations presented with an HEC. These results emphasized the need for prenatal cystinuria screening using classical third-trimester ultrasound scan and the early management of suspected newborns. PMID: 28646536 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - June 24, 2017 Category: Genetics & Stem Cells Authors: Tostivint I, Royer N, Nicolas M, Bourillon A, Czerkiewicz I, Becker PH, Muller F, Benoist JF Tags: Clin Genet Source Type: research

A genetic epidemiology study of Congenital Adrenal Hyperplasia in Italy.
meo G Abstract Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency (21OHD-CAH) is an autosomal recessive disorder affecting steroidogenesis, due to mutations in CYP21A2 (6p21.3). 21OHD-CAH neonatal screening is based on 17-hydroxyprogesterone (17OHP) serum levels, showing high type I error rate and low sensitivity to mild CAH forms. Here, we used an epidemiological approach, which estimates the allelic frequency (q) of an autosomal recessive disorder using the proportion of homozygous patients, the mutational spectrum and the inbreeding coefficient in a sample of affected individuals. We applied this a...
Source: Clinical Genetics - June 23, 2017 Category: Genetics & Stem Cells Authors: Gialluisi A, Menabò S, Baldazzi L, Casula L, Meloni A, Farci MC, Mariotti S, Balestrino L, Ortolano R, Murru S, Carcassi C, Loche S, Balsamo A, Romeo G Tags: Clin Genet Source Type: research

Increasing awareness and knowledge of lifestyle recommendations for cancer prevention in Lynch Syndrome carriers: randomized controlled trial.
In conclusion, provision of WCRF-NL health promotion materials increases awareness and knowledge of lifestyle recommendations for cancer prevention among LS mutation carriers without causing additional distress, but does not affect adherence. PMID: 28632915 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - June 20, 2017 Category: Genetics & Stem Cells Authors: Vrieling A, Visser A, Hoedjes M, Hurks M, Gómez García E, Hoogerbrugge N, Kampman E Tags: Clin Genet Source Type: research

Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis.
In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies. PMID: 28632965 [PubMed - as supplied by publisher] (Source: Clinical Genetics)
Source: Clinical Genetics - June 20, 2017 Category: Genetics & Stem Cells Authors: Papazachariou L, Papagregoriou G, Hadjipanagi D, Demosthenous P, Voskarides K, Koutsofti C, Stylianou K, Ioannou P, Xydakis D, Tzanakis I, Papadaki A, Kallivretakis N, Nikolakakis N, Perysinaki G, Gale DP, Diamantopoulos A, Goudas P, Goumenos D, Soloukide Tags: Clin Genet Source Type: research

Fragile X syndrome: an overview and update of the FMR1 gene.
Abstract Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and the leading form of the monogenic cause of autism. FMR1 premutation is the first single-gene cause of primary ovarian failure (FXPOI) and one of the most common causes of ataxia (FXTAS), multiple additional phenotypes such as fibromyalgia, hypothyroidism, migraine headaches, sleep disturbances, sleep apnea, restless legs syndrome, central pain syndrome, neuropathy and neuropsychiatric alterations has been described. Clinical involvement in men and women carrying the FMR1 premutation currently constitutes a real heal...
Source: Clinical Genetics - June 15, 2017 Category: Genetics & Stem Cells Authors: Mila M, Alvarez-Mora MI, Madrigal I, Rodriguez-Revenga L Tags: Clin Genet Source Type: research

Further delineation of the phenotype caused by biallelic variants in the WDR4 gene.
We report here two sisters harboring compound heterozygous variants of WDR4. Their phenotype differs from that of the first two described patients: they both have a severe microcephaly but only one of the two sisters had a head circumference at birth below -2 SD, their intellectual deficiency is less severe, and they have a GH deficiency and a partial hypogonadotropic hypogonadotropism. One of the two variants is a frameshift mutation, and the other one is a missense occurring in the same nucleotide affected by the first reported pathogenic variant, which could therefore be a mutational hot spot. The description of these t...
Source: Clinical Genetics - June 15, 2017 Category: Genetics & Stem Cells Authors: Trimouille A, Lasseaux E, Barat P, Deiller C, Drunat S, Rooryck C, Arveiler B, Lacombe D Tags: Clin Genet Source Type: research

Genetic epidemiology of Familial Mediterranean Fever through integrative analysis of whole genome and exome sequences from Middle East and North Africa.
Abstract Familial Mediterranean fever (FMF), an autosomal recessive and rare autoinflammatory disease is caused by genetic mutations in the MEFV gene and is highly prevalent in the Mediterranean basin. Though the carrier frequency of specific disease variants in the MEFV gene has been reported from isolated studies, a comprehensive view of variants in the Mediterranean region has not been possible due to paucity of data. The recent availability of whole-genome and whole-exome datasets prompted us to study the genetic epidemiology of MEFV variants in the region. We assembled data from five datasets encompassing who...
Source: Clinical Genetics - June 9, 2017 Category: Genetics & Stem Cells Authors: Koshy R, Sivadas A, Scaria V Tags: Clin Genet Source Type: research

Large-scale Study of Clinical and Biochemical Characteristics of Chinese Patients Diagnosed with Krabbe Disease.
This study investigated 22 unrelated Chinese patients, including their clinical presentations, plasma psychosine levels and GALC gene mutations. We found the late-onset form of KD present in 82% of the patients in our study, which was more prevalent than in patients from other populations. Plasma psychosine levels were elevated in KD, which were correlated with the severity of clinical presentations. Sanger sequencing identified 8 novel mutations, including 7 missense mutations, p.H253Y, p.S259L, p.P318L, p.F350V, p.T428A, p.L530P, p.G586D, and 1 splicing mutation, c.1251+1G>A. Quantitative real-time PCR and multiplex l...
Source: Clinical Genetics - June 9, 2017 Category: Genetics & Stem Cells Authors: Zhao S, Zhan X, Wang Y, Ye J, Han L, Qiu W, Gao X, Gu X, Zhang H Tags: Clin Genet Source Type: research

Genetic Study of Early-onset Graves' Disease in the Chinese Han Population.
Abstract Graves' disease (GD) is a complex autoimmune disorder in which genetic and environmental factors are both involved in the pathogenesis. Early-onset patients have a shorter exposure time to environmental factors and are, therefore, good models to help understand the genetic architecture of GD. Based on previous studies of early-onset GD, eleven single nucleotide polymorphisms (SNPs) and their related SNPs (R(2)> 0.6), SNPs located within a ± 1-Mb region of the FOXP3 gene, and twenty validated GD-risk SNPs were selected and screened for genotyping in 3,735 GD and 4,893 control patien...
Source: Clinical Genetics - June 9, 2017 Category: Genetics & Stem Cells Authors: Yuan FF, Ye XP, Liu W, Xue LQ, Ma YR, Zhang LL, Zhang MM, Sun F, Wan YY, Zhang QY, Zhao SX, Song HD, China Consortium for the Genetics of Autoimmune Thyroid Disease Tags: Clin Genet Source Type: research

Novel biallelic mutations in the PNPT1 gene encoding a mitochondrial-RNA-import protein PNPase cause delayed myelination.
We report here two siblings with PNPT1 mutations who presented delayed myelination as well as mitochondrial dysfunction. We identified compound heterozygous mutations (c.227G>A; p.Gly76Asp and c.574C>T; p.Arg192*) in PNPT1 by quartet whole-exome sequencing. Analyses of skin fibroblasts from the patient showed that PNPase expression was markedly decreased and that import of the small RNA RNase P into mitochondria was impaired. Exogenous expression of wild-type PNPT1, but not mutants, rescued ATP production in patient skin fibroblasts, suggesting the pathogenicity of the identified mutations. Our cases expand the pheno...
Source: Clinical Genetics - June 8, 2017 Category: Genetics & Stem Cells Authors: Sato R, Arai-Ichinoi N, Kikuchi A, Matsuhashi T, Numata-Uematsu Y, Uematsu M, Fujii Y, Murayama K, Ohtake A, Abe T, Kure S Tags: Clin Genet Source Type: research

Distinguishing pathogenic mutations from background genetic noise in cardiology: the use of large genome databases for genetic interpretation.
Abstract Advances in clinical genetic testing has led to increased insight into the human genome, including how challenging it is to interpret rare genetic variation. In some cases, the ability to detect genetic mutations exceeds the ability to understand their clinical impact, limiting the advantage of these technologies. Obstacles in genomic medicine are many and include: understanding the level of certainty/uncertainty behind pathogenicity determination, the numerous different variant interpretation-guidelines used by clinical laboratories, delivering the certain or uncertain result to the patient, helping pati...
Source: Clinical Genetics - June 6, 2017 Category: Genetics & Stem Cells Authors: Ghouse J, Skov MW, Bigseth RS, Ahlberg G, Kanters JK, Olesen MS Tags: Clin Genet Source Type: research