PCNT point mutations and familial intracranial aneurysms.

Neurology. 2018 Nov 09;:

Authors: Lorenzo-Betancor O, Blackburn PR, Edwards E, Vázquez-do-Campo R, Klee EW, Labbé C, Hodges K, Glover P, Sigafoos AN, Soto AI, Walton RL, Doxsey S, Bober MB, Jennings S, Clark KJ, Asmann Y, Miller D, Freeman WD, Meschia J, Ross OA

Abstract
OBJECTIVE: To identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing.
METHODS: We performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants.
RESULTS: We identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases.
CONCLUSION: The PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (microcephalic osteodysplastic primordial dwarfism type II), and ≈50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model (Pcnt -/-) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease.

PMID: 30413633 [PubMed - as supplied by publisher]

Biallelic COLGALT1 variants are associated with cerebral small vessel disease.

Ann Neurol. 2018 Nov 09;:

Authors: Miyatake S, Schneeberger S, Koyama N, Yokochi K, Ohmura K, Shiina M, Mori H, Koshimizu E, Imagawa E, Uchiyama Y, Mitsuhashi S, Frith MC, Fujita A, Satoh M, Taguri M, Tomono Y, Takahashi K, Doi H, Takeuchi H, Nakashima M, Mizuguchi T, Takata A, Miyake N, Saitsu H, Tanaka F, Ogata K, Hennet T, Matsumoto N

Abstract
OBJECTIVE: Approximately 5% of cerebral small vessel diseases are hereditary, which include COL4A1/COL4A2-related disorders. COL4A1/COL4A2 encode type IV collagen α1/2 chains in the basement membranes of cerebral vessels. COL4A1/COL4A2 mutations impair the secretion of collagen to the extracellular matrix, thereby resulting in vessel fragility. The diagnostic yield for COL4A1/COL4A2 variants is around 20%-30%, suggesting other mutated genes might be associated with this disease. This study aimed to identify novel genes that cause COL4A1/COL4A2-related disorders.
METHODS: Whole exome sequencing was performed in two families with suspected COL4A1/COL4A2-related disorders. We validated the role of COLGALT1 variants by constructing a 3D structural model, evaluating ColGalT1 protein expression and ColGalT activity by western blotting and collagen galactosyltransferase assays, and performing in vitro RNA interference and rescue experiments.
RESULTS: Exome sequencing demonstrated biallelic variants in COLGALT1 encoding collagen β (1-O) galactosyltransferase 1, which was involved in the post-translational modification of type IV collagen in two unrelated patients: c.452T>G (p.Leu151Arg) and c.1096delG (p.Glu366Argfs*15) in Patient 1, and c.460G>C (p.Ala154Pro) and c.1129G>C (p.Gly377Arg) in Patient 2. 3D model analysis suggested that p.Leu151Arg and p.Ala154Pro destabilized protein folding, which impaired enzymatic activity. ColGalT1 protein expression and ColGalT activity in Patient 1 were undetectable. RNA interference studies demonstrated that reduced ColGalT1 altered COL4A1 secretion, and rescue experiments showed that mutant COLGALT1 insufficiently restored COL4A1 production in cells compared with wild-type.
INTERPRETATION: Biallelic COLGALT1 variants cause cerebral small vessel abnormalities through a common molecular pathogenesis with COL4A1/COL4A2-related disorders. This article is protected by copyright. All rights reserved.

PMID: 30412317 [PubMed - as supplied by publisher]

Novel SPEG mutations in congenital myopathies: Genotype-phenotype correlations.

Muscle Nerve. 2018 Nov 09;:

Authors: Qualls AE, Donkervoort S, Herkert JC, D'Gama AM, Bharucha-Goebel D, Collins J, Chao KR, Foley AR, Schoots MH, Jongbloed JDH, Bönnemann CG, Agrawal PB

Abstract
INTRODUCTION: Centronuclear myopathies (CNMs) are a subtype of congenital myopathies (CMs) characterized by muscle weakness, predominant type 1 fibers, and increased central nuclei. SPEG (striated preferentially expressed protein kinase) mutations have recently been identified in seven CM patients (six with CNMs). We report two additional patients with SPEG mutations expanding the phenotype and evaluate genotype-phenotype correlations associated with SPEG mutations.
METHODS/RESULTS: Using whole exome/genome sequencing in CM families, we identified novel recessive SPEG mutations in two patients. Patient 1, with severe muscle weakness requiring respiratory support, dilated cardiomyopathy, ophthalmoplegia, and findings of non-specific CM on muscle biopsy carried a homozygous SPEG mutation (p.Val3062del). Patient 2, with milder muscle weakness, ophthalmoplegia, and CNM carried compound heterozygous mutations (p.Leu728Argfs*82) and (p.Val2997Glyfs*52).
DISCUSSION: The two patients add insight into genotype-phenotype correlations of SPEG-associated CMs. Clinicians should consider evaluating a CM patient for SPEG mutations even in the absence of CNM features. This article is protected by copyright. All rights reserved.

PMID: 30412272 [PubMed - as supplied by publisher]

Whole-exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data.

Mol Genet Genomic Med. 2018 Nov 08;:

Authors: Gianferante DM, Rotunno M, Dean M, Zhou W, Hicks BD, Wyatt K, Jones K, Wang M, Zhu B, Goldstein AM, Mirabello L

Abstract
BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder with variable expression and nearly complete penetrance. PTCH1 is the major susceptibility locus and has no known hot spots or genotype-phenotype relationships.
METHODS: We evaluated 18 NBCCS National Cancer Institute (NCI) families plus PTCH1 data on 333 NBCCS disease-causing mutations (DM) reported in the Human Gene Mutation Database (HGMD). National Cancer Institute families underwent comprehensive genomic evaluation, and clinical data were extracted from NCI and HGMD cases. Genotype-phenotype relationships were analyzed using Fisher's exact tests focusing on mutation type and PTCH1 domains.
RESULTS: PTCH1 pathogenic mutations were identified in 16 of 18 NCI families, including three previously mutation-negative families. PTCH1 mutations were spread across the gene with no hot spot. After adjustment for multiple tests, a statistically significant genotype-phenotype association was observed for developmental delay and gross deletion-insertions (p = 9.0 × 10-6 ), and suggestive associations between falx cerebri calcification and all transmembrane domains (p = 0.002) and severe outcomes and gross deletion-insertions (p = 4.0 × 10-4 ).
CONCLUSION: Overall, 89% of our NCI families had a pathogenic PTCH1 mutation. The identification of PTCH1 mutations in previously mutation-negative families underscores the importance of repeated testing when new technologies become available. Additional clinical information linked to mutation databases would enhance follow-up and future studies of genotype-phenotype relationships.

PMID: 30411536 [PubMed - as supplied by publisher]

Epileptic Encephalopathy and Cerebellar Atrophy Resulting from Compound Heterozygous CACNA2D2 Variants.

Case Rep Genet. 2018;2018:6308283

Authors: Butler KM, Holt PJ, Milla SS, da Silva C, Alexander JJ, Escayg A

Abstract
CACNA2D2 encodes an auxiliary subunit of the voltage-dependent calcium channel. To date, there have only been two reports of individuals with early-infantile epileptic encephalopathy due to CACNA2D2 mutations. In both reports, patients were homozygous for the identified variants. Here, we report a patient with epileptic encephalopathy and cerebellar atrophy who was found to have two novel variants in the CACNA2D2 gene: c.782C>T (p.Pro261Leu) and c.3137T>C (p.Leu1046Pro), by whole-exome sequencing. The variants were shown to be inherited in trans and the unaffected parents were confirmed to be heterozygous carriers. This is the third report of recessive CACNA2D2 variants associated with disease and the first report of compound heterozygous variants. The clinical description of this new case highlights the phenotypic similarities amongst individuals with CACNA2D2-related disease and suggests that CACNA2D2 should be considered as a differential diagnosis in individuals with cerebellar dysfunction and multiple seizure types that begin in the first year of life.

PMID: 30410802 [PubMed]

O'Sullivan-McLeod syndrome: Unmasking a rare atypical motor neuron disease.

Rev Neurol (Paris). 2018 Nov 05;:

Authors: Pinto WBVR, Nunes P, Lima E Teixeira I, Assis ACD, Naylor FGM, Chieia MAT, Souza PVS, A S B Oliveira

Abstract
Atypical motor neuron disease represents a rare heterogeneous group of neurodegenerative disorders with clinical, genetic and neuroimaging features distinct from those of the classic spinal or bulbar-onset amyotrophic lateral sclerosis (ALS). O'Sullivan-McLeod syndrome represents an extremely rare lower motor neuronopathy with early adult-onset distal amyotrophy and weakness in the upper limbs with asymmetrical involvement. To add to the few case series and epidemiological and genetic studies describing this variant syndrome, our team here presents a series of seven unrelated Brazilian patients with O'Sullivan-McLeod syndrome in a detailed review of their clinical, neuroimaging, laboratory and neurophysiological findings. A male-to-female ratio of 2.5 to 1 and a mean age at onset of 34.3years was observed, with a mean time delay of 6.6years between symptom-onset and a definitive diagnosis. A positive family history was observed in one case, yet whole-exome sequencing results were negative. Neuroimaging studies were unremarkable. All cases presented with chronic denervation restricted to cervical myotomes and normal sensory nerve conduction studies. This case series, one of the largest groups of patients with O'Sullivan-McLeod syndrome reported in the literature, confirms the sporadic nature of the condition and the difficulties faced in arriving at a definite diagnosis, and also expands the age limit in late adult-onset cases.

PMID: 30409480 [PubMed - as supplied by publisher]

European paediatric non-alcoholic fatty liver disease registry (EU-PNAFLD): Design and rationale.

Contemp Clin Trials. 2018 Nov 05;:

Authors: Mann JP, Vreugdenhil A, Socha P, Jańczyk W, Baumann U, Rajwal S, Casswall T, Marcus C, van Mourik I, O'Rahilly S, Savage DB, Noble-Jamieson G, Lacaille F, Dabbas M, Dubern B, Kelly DA, Nobili V, Anstee QM

Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in children and has the potential to progress to advanced fibrosis/cirrhosis, end-stage liver disease and hepatocellular carcinoma. However, the natural history of the condition is poorly understood and there are no approved treatments. The European Paediatric Non-Alcoholic Fatty Liver Disease Registry (EU-PNAFLD) is a multi-centre registry of paediatric NAFLD that will serve as a prospective, observational, natural history study and provide a tractable back-bone to support recruitment into subsequent interventional trials. Collection of samples into a bio-repository will facilitate translational studies, including genome sequencing and metabolomics. EU-PNAFLD will work closely alongside the existing adult European NAFLD Registry to obtain data on clinical outcomes after 20-30 years. Through an international, well-characterised large-scale cohort, EU-PNAFLD will address the key questions in paediatric NAFLD and benefit patients with the condition.

PMID: 30408605 [PubMed - as supplied by publisher]

Mitochondrial and nuclear disease panel (Mito-aND-Panel): Combined sequencing of mitochondrial and nuclear DNA by a cost-effective and sensitive NGS-based method.

Mol Genet Genomic Med. 2018 Nov 08;:

Authors: Abicht A, Scharf F, Kleinle S, Schön U, Holinski-Feder E, Horvath R, Benet-Pagès A, Diebold I

Abstract
BACKGROUND: The diagnosis of mitochondrial disorders is challenging because of the clinical variability and genetic heterogeneity of these conditions. Next-Generation Sequencing (NGS) technology offers a robust high-throughput platform for nuclear and mitochondrial DNA (mtDNA) analyses.
METHOD: We developed a custom Agilent SureSelect Mitochondrial and Nuclear Disease Panel (Mito-aND-Panel) capture kit that allows parallel enrichment for subsequent NGS-based sequence analysis of nuclear mitochondrial disease-related genes and the complete mtDNA genome. Sequencing of enriched mtDNA simultaneously with nuclear genes was compared with the separated sequencing of the mitochondrial genome and whole exome sequencing (WES).
RESULTS: The Mito-aND-Panel permits accurate detection of low-level mtDNA heteroplasmy due to a very high sequencing depth compared to standard diagnostic procedures using Sanger sequencing/SNaPshot and WES which is crucial to identify maternally inherited mitochondrial disorders.
CONCLUSION: We established a NGS-based method with combined sequencing of the complete mtDNA and nuclear genes which enables a more sensitive heteroplasmy detection of mtDNA mutations compared to traditional methods. Because the method promotes the analysis of mtDNA variants in large cohorts, it is cost-effective and simple to setup, we anticipate this is a highly relevant method for sequence-based genetic diagnosis in clinical diagnostic applications.

PMID: 30406974 [PubMed - as supplied by publisher]

Ataxia-telangiectasia with a novel ATM gene mutation and Burkitt leukemia: A case report.

Mol Clin Oncol. 2018 Nov;9(5):493-498

Authors: Ye F, Chai W, Yang M, Xie M, Yang L

Abstract
Ataxia-telangiectasia (A-T) is an infrequent autosomal recessive disorder that involves multiple systems and is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, radiosensitivity, immune deficiency with recurrent respiratory infections, and a tendency to develop lymphoid malignancies. A-T is caused by mutations in the ATM gene, with >1,000 mutations reported to date and gradually increasing in number. Patients with A-T have an increased incidence of cancers. The aim of the present study was to retrospectively review the case of a patient who presented at the age of 5 years with cerebellar ataxia without telangiectasia, and was diagnosed with Burkitt leukemia by bone marrow biopsy and molecular testing at the age of 7 years at the Xiangya Hospital of Central South University (Changsha, China). The patient received chemotherapy with the pediatric CCCG-BNHL-2015 regimen (R4 group) and achieved a complete remission after 2 courses. However, recurrent respiratory infections and thrombosis occurred during chemotherapy. The diagnosis of A-T was confirmed by uncovering two variants of the ATM gene, including c.742C>T (p.R248X; rs730881336) in exon 7 and c.6067-c.6068 ins GAGGGAAGAT in exon 41 by whole-exome sequencing. Unfortunately, the patient's parents refused follow-up treatment and he succumbed to recurrent severe infections 4 months after the diagnosis of Burkitt leukemia. The diagnosis of A-T may be challenging, as its phenotype can be incomplete early in the course of the disease. Detailed medical history, characteristic clinical manifestations and increasingly developed exome sequencing techniques may be helpful in diagnosing this rare disease. Management should be based on multidisciplinary guidance and other treatment options must be investigated in the future.

PMID: 30402232 [PubMed]

Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population.

Biomed Rep. 2018 Nov;9(5):383-404

Authors: Yamada Y, Yasukochi Y, Kato K, Oguri M, Horibe H, Fujimaki T, Takeuchi I, Sakuma J

Abstract
Early-onset coronary artery disease (CAD) has a strong genetic component. Although genome-wide association studies have identified various genes and loci significantly associated with CAD mainly in European populations, genetic variants that contribute toward susceptibility to this condition in Japanese patients remain to be definitively identified. In the present study, exome-wide association studies (EWASs) were performed to identify genetic variants that confer susceptibility to early-onset CAD in Japanese. A total of 7,256 individuals aged ≤65 years were enrolled in the present study. EWAS were conducted on 1,482 patients with CAD and 5,774 healthy controls. Genotyping of single nucleotide polymorphisms (SNPs) was performed using Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The association between allele frequencies for 31,465 SNPs that passed quality control and CAD was examined using Fisher's exact test. To compensate for multiple comparisons of allele frequencies with CAD, a false discovery rate (FDR) of <0.05 was applied for statistically significant associations. The association between allele frequencies for 31,465 SNPs and CAD, as determined by Fisher's exact test, demonstrated that 170 SNPs were significantly (FDR <0.05) associated with CAD. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension, diabetes mellitus and dyslipidemia revealed that 162 SNPs were significantly (P<0.05) associated with CAD. A stepwise forward selection procedure was performed to examine the effects of genotypes for the 162 SNPs on CAD. The 54 SNPs were significant (P<0.05) and independent [coefficient of determination (R2), 0.0008 to 0.0297] determinants of CAD. These SNPs together accounted for 15.5% of the cause of CAD. Following examination of results from previous genome-wide association studies and linkage disequilibrium of the identified SNPs, 21 genes (RNF2, YEATS2, USP45, ITGB8, TNS3, FAM170B-AS1, PRKG1, BTRC, MKI67, STIM1, OR52E4, KIAA1551, MON2, PLUT, LINC00354, TRPM1, ADAT1, KRT27, LIPE, GFY and EIF3L) and five chromosomal regions (2p13, 4q31.2, 5q12, 13q34 and 20q13.2) that were significantly associated with CAD were newly identified in the present study. Gene ontology analysis demonstrated that various biological functions were predicted in the 18 genes identified in the present study. The network analysis revealed that the 18 genes had potential direct or indirect interactions with the 30 genes previously revealed to be associated with CAD or with the 228 genes identified in previous genome-wide association studies. The present study newly identified 26 loci that confer susceptibility to CAD. Determination of genotypes for the SNPs at these loci may prove informative for assessment of the genetic risk for CAD in Japanese patients.

PMID: 30402224 [PubMed]

Insights into the genomic landscape of MYD88 wild-type Waldenström macroglobulinemia.

Blood Adv. 2018 Nov 13;2(21):2937-2946

Authors: Hunter ZR, Xu L, Tsakmaklis N, Demos MG, Kofides A, Jimenez C, Chan GG, Chen J, Liu X, Munshi M, Gustine J, Meid K, Patterson CJ, Yang G, Dubeau T, Samur MK, Castillo JJ, Anderson KC, Munshi NC, Treon SP

Abstract
Activating MYD88 mutations are present in 95% of Waldenström macroglobulinemia (WM) patients, and trigger NF-κB through BTK and IRAK. The BTK inhibitor ibrutinib is active in MYD88-mutated (MYD88 MUT ) WM patients, but shows lower activity in MYD88 wild-type (MYD88 WT ) disease. MYD88 WT patients also show shorter overall survival, and increased risk of disease transformation in some series. The genomic basis for these findings remains to be clarified. We performed whole exome and transcriptome sequencing of sorted tumor samples from 18 MYD88 WT patients and compared findings with WM patients with MYD88 MUT disease. We identified somatic mutations predicted to activate NF-κB (TBL1XR1, PTPN13, MALT1, BCL10, NFKB2, NFKBIB, NFKBIZ, and UDRL1F), impart epigenomic dysregulation (KMT2D, KMT2C, and KDM6A), or impair DNA damage repair (TP53, ATM, and TRRAP). Predicted NF-κB activating mutations were downstream of BTK and IRAK, and many overlapped with somatic mutations found in diffuse large B-cell lymphoma. A distinctive transcriptional profile in MYD88 WT WM was identified, although most differentially expressed genes overlapped with MYD88 MUT WM consistent with the many clinical and morphological characteristics that are shared by these WM subgroups. Overall survival was adversely affected by mutations in DNA damage response in MYD88 WT WM patients. The findings depict genomic and transcriptional events associated with MYD88 WT WM and provide mechanistic insights for disease transformation, decreased ibrutinib activity, and novel drug approaches for this population.

PMID: 30401751 [PubMed - in process]

Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay.

Am J Hum Genet. 2018 Nov 01;103(5):794-807

Authors: Morimoto M, Waller-Evans H, Ammous Z, Song X, Strauss KA, Pehlivan D, Gonzaga-Jauregui C, Puffenberger EG, Holst CR, Karaca E, Brigatti KW, Maguire E, Coban-Akdemir ZH, Amagata A, Lau CC, Chepa-Lotrea X, Macnamara E, Tos T, Isikay S, Nehrebecky M, Overton JD, Klein M, Markello TC, Posey JE, Adams DR, Lloyd-Evans E, Lupski JR, Gahl WA, Malicdan MCV

Abstract
Ca2+ signaling is vital for various cellular processes including synaptic vesicle exocytosis, muscle contraction, regulation of secretion, gene transcription, and cellular proliferation. The endoplasmic reticulum (ER) is the largest intracellular Ca2+ store, and dysregulation of ER Ca2+ signaling and homeostasis contributes to the pathogenesis of various complex disorders and Mendelian disease traits. We describe four unrelated individuals with a complex multisystem disorder characterized by woolly hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and global developmental delay. Through whole-exome sequencing and family-based genomics, we identified bi-allelic variants in CCDC47 that encodes the Ca2+-binding ER transmembrane protein CCDC47. CCDC47, also known as calumin, has been shown to bind Ca2+ with low affinity and high capacity. In mice, loss of Ccdc47 leads to embryonic lethality, suggesting that Ccdc47 is essential for early development. Characterization of cells from individuals with predicted likely damaging alleles showed decreased CCDC47 mRNA expression and protein levels. In vitro cellular experiments showed decreased total ER Ca2+ storage, impaired Ca2+ signaling mediated by the IP3R Ca2+ release channel, and reduced ER Ca2+ refilling via store-operated Ca2+ entry. These results, together with the previously described role of CCDC47 in Ca2+ signaling and development, suggest that bi-allelic loss-of-function variants in CCDC47 underlie the pathogenesis of this multisystem disorder.

PMID: 30401460 [PubMed - in process]

Identification of Elongated Primary Cilia with Impaired Mechanotransduction in Idiopathic Scoliosis Patients.

Sci Rep. 2017 03 14;7:44260

Authors: Oliazadeh N, Gorman KF, Eveleigh R, Bourque G, Moreau A

Abstract
The primary cilium is an outward projecting antenna-like organelle with an important role in bone mechanotransduction. The capacity to sense mechanical stimuli can affect important cellular and molecular aspects of bone tissue. Idiopathic scoliosis (IS) is a complex pediatric disease of unknown cause, defined by abnormal spinal curvatures. We demonstrate significant elongation of primary cilia in IS patient bone cells. In response to mechanical stimulation, these IS cells differentially express osteogenic factors, mechanosensitive genes, and signaling genes. Considering that numerous ciliary genes are associated with a scoliosis phenotype, among ciliopathies and knockout animal models, we expected IS patients to have an accumulation of rare variants in ciliary genes. Instead, our SKAT-O analysis of whole exomes showed an enrichment among IS patients for rare variants in genes with a role in cellular mechanotransduction. Our data indicates defective cilia in IS bone cells, which may be linked to heterogeneous gene variants pertaining to cellular mechanotransduction.

PMID: 28290481 [PubMed - indexed for MEDLINE]

PTRHD1 Loss-of-function mutation in an african family with juvenile-onset Parkinsonism and intellectual disability.

Mov Disord. 2018 Nov 06;:

Authors: Kuipers DJS, Carr J, Bardien S, Thomas P, Sebate B, Breedveld GJ, van Minkelen R, Brouwer RWW, van Ijcken WFJ, van Slegtenhorst MA, Bonifati V, Quadri M

Abstract
BACKGROUND: The genetic bases of PD in sub-Saharan African (SSA) populations remain poorly characterized, and analysis of SSA families with PD might lead to the discovery of novel disease-related genes.
OBJECTIVES: To investigate the clinical features and identify the disease-causing gene in a black South African family with 3 members affected by juvenile-onset parkinsonism and intellectual disability.
METHODS: Clinical evaluation, neuroimaging studies, whole-exome sequencing, homozygosity mapping, two-point linkage analysis, and Sanger sequencing of candidate variants.
RESULT: A homozygous 28-nucleotide frameshift deletion in the PTRHD1 coding region was identified in the 3 affected family members and linked to the disease with genome-wide significant evidence. PTRHD1 was recently nominated as the disease-causing gene in two Iranian families, each containing 2 siblings with similar phenotypes and homozygous missense mutations.
CONCLUSION: Together with the previous reports, we provide conclusive evidence that loss-of-function mutations in PTRHD1 cause autosomal-recessive juvenile parkinsonism and intellectual disability. © 2018 International Parkinson and Movement Disorder Society.

PMID: 30398675 [PubMed - as supplied by publisher]

De novo nonsense mutation in WHSC1 (NSD2) in patient with intellectual disability and dysmorphic features.

J Hum Genet. 2018 Jul;63(8):919-922

Authors: Lozier ER, Konovalov FA, Kanivets IV, Pyankov DV, Koshkin PA, Baleva LS, Sipyagina AE, Yakusheva EN, Kuchina AE, Korostelev SA

Abstract
Intellectual disability is the most common developmental disorder caused by chromosomal aberrations as well as single-nucleotide variants (SNVs) and small insertions/deletions (indels). Here we report identification of a novel, probably pathogenic mutation in the WHSC1 gene in a patient case with phenotype overlapping the features of Wolf-Hirschhorn syndrome. Deletions involving WHSC1 (Wolf-Hirschhorn syndrome candidate 1 gene) were described earlier in patients with Wolf-Hirschhorn syndrome. However, to our knowledge, single-point mutations in WHSC1 associated with any intellectual deficiency syndromes have not been reported. Using whole exome sequencing, we found a de novo nonsense mutation in WHSC1 (c.3412C>T, p.Arg1138Ter, NM_001042424.2) in patient with syndromic intellectual disability. This finding is challenging regarding a possible causative role of WHSC1 in intellectual disability syndromes, specifically Wolf-Hirschhorn syndrome. From the clinical standpoint, our finding suggests that next-generation sequencing along with chromosome microarray analysis (CMA) might be useful in genetic testing for patients with intellectual disability and dysmorphic features.

PMID: 29760529 [PubMed - indexed for MEDLINE]

LRRTM4-C538Y novel gene mutation is associated with hereditary macular degeneration with novel dysfunction of ON-type bipolar cells.

J Hum Genet. 2018 Aug;63(8):893-900

Authors: Kawamura Y, Suga A, Fujimaki T, Yoshitake K, Tsunoda K, Murakami A, Iwata T

Abstract
The macula is a unique structure in higher primates, where cone and rod photoreceptors show highest density in the fovea and the surrounding area, respectively. The hereditary macular dystrophies represent a heterozygous group of rare disorders characterized by central visual loss and atrophy of the macula and surrounding retina. Here we report an atypical absence of ON-type bipolar cell response in a Japanese patient with autosomal dominant macular dystrophy (adMD). To identify a causal genetic mutation for the adMD, we performed whole-exome sequencing (WES) on four affected and four-non affected members of the family for three generations, and identified a novel p.C538Y mutation in a post-synaptic gene, LRRTM4. WES analysis revealed seven rare genetic variations in patients. We further referred to our in-house WES data from 1360 families with inherited retinal diseases, and found that only p.C538Y mutation in LRRTM4 was associated with adMD-affected patients. Combinatorial filtration using public database of single-nucleotide polymorphism frequency and genotype-phenotype annotated database identified novel mutation in atypical adMD.

PMID: 29760528 [PubMed - indexed for MEDLINE]

Diagnostic Application of Targeted Next-Generation Sequencing of 80 Genes Associated with Disorders of Sexual Development.

Sci Rep. 2017 03 15;7:44536

Authors: Fan Y, Zhang X, Wang L, Wang R, Huang Z, Sun Y, Yao R, Huang X, Ye J, Han L, Qiu W, Zhang H, Liang L, Gu X, Yu Y

Abstract
Disorders of sexual development (DSD) are estimated to occur in 1 of 4500 births. Since the genetic etiology of DSD is highly heterogeneous, obtaining a definitive molecular diagnosis by single gene test is challenging. Utilizing a high-throughput sequencing upfront is proposed as an efficient approach to aid in the diagnosis. This study aimed to examine the diagnostic yield of next-generation sequencing in DSD. 32 DSD patients that previously received clinical examinations and single gene tests were selected, with or without a diagnosis. Prior single gene tests were masked, and then samples went through targeted next-generation sequencing of 80 genes from which the diagnostic yield was assessed. A likely diagnosis, with pathogenic or likely pathogenic variants identified, was obtained from nine of the 32 patients (i.e., 28.1%, versus 10% by single gene tests). In another five patients (15.6%), variants of uncertain significance were found. Among 18 variants identified (i.e., 17 single nucleotide variants and one small deletion), eight had not been previously reported. This study supports the notion that next-generation sequencing can be an efficient tool in the clinical diagnosis and variant discovery in DSD.

PMID: 28295047 [PubMed - indexed for MEDLINE]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

(exome OR "exome sequencing") AND disease

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14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

(exome OR "exome sequencing") AND disease

These pubmed results were generated on 2018/11/06

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability.

Am J Hum Genet. 2018 Nov 01;103(5):808-816

Authors: Schlingmann KP, Bandulik S, Mammen C, Tarailo-Graovac M, Holm R, Baumann M, König J, Lee JJY, Drögemöller B, Imminger K, Beck BB, Altmüller J, Thiele H, Waldegger S, Van't Hoff W, Kleta R, Warth R, van Karnebeek CDM, Vilsen B, Bockenhauer D, Konrad M

Abstract
Over the last decades, a growing spectrum of monogenic disorders of human magnesium homeostasis has been clinically characterized, and genetic studies in affected individuals have identified important molecular components of cellular and epithelial magnesium transport. Here, we describe three infants who are from non-consanguineous families and who presented with a disease phenotype consisting of generalized seizures in infancy, severe hypomagnesemia, and renal magnesium wasting. Seizures persisted despite magnesium supplementation and were associated with significant intellectual disability. Whole-exome sequencing and conventional Sanger sequencing identified heterozygous de novo mutations in the catalytic Na+, K+-ATPase α1 subunit (ATP1A1). Functional characterization of mutant Na+, K+-ATPase α1 subunits in heterologous expression systems revealed not only a loss of Na+, K+-ATPase function but also abnormal cation permeabilities, which led to membrane depolarization and possibly aggravated the effect of the loss of physiological pump activity. These findings underline the indispensable role of the α1 isoform of the Na+, K+-ATPase for renal-tubular magnesium handling and cellular ion homeostasis, as well as maintenance of physiologic neuronal activity.

PMID: 30388404 [PubMed - in process]