Genetic contribution of SUN5 mutations to acephalic spermatozoa in Fujian China.

Gene. 2018 Jan 10;:

Authors: Sha YW, Xu X, Ji ZY, Lin SB, Wang X, Qiu PP, Zhou Y, Mei LB, Su ZY, Li L, Li P

Abstract
Acephalic spermatozoa is an extremely rare disease associated with primary infertility. A recent study showed that genetic alterations in the SUN5 gene lead to this disease, and SUN5 mutations could explain the disease in about half of the patients. Therefore, in the present study, to re-visit the genetic contribution of SUN5 mutations to acephalic spermatozoa, we recruited 15 unrelated affected individuals and screened the SUN5 gene for mutations by whole-exome sequencing (WES) and Sanger sequencing. Five of the 15 (33.33%) subjects were found to carry the same homozygous mutation in the SUN5 gene c.381delA (p.V128Sfs*7). Neither homozygous nor compound heterozygous mutations in SUN5 were found in the other 10 patients. The c.381delA mutation resulted in the truncation of the SUN5 protein and decreased the expression and altered the distribution of the outer dense fiber 1 (ODF1) protein. Thus, in our study SUN5 mutations accounted for only one-third of the patients in our cohort, which is lower than the percentage reported previously. Thus, our study suggests that the contribution of SUN5 mutations to acephalic spermatozoa might not be as high as described previously. These results will help in the genetic counseling of patients with acephalic spermatozoa.

PMID: 29331481 [PubMed - as supplied by publisher]

A De Novo FOXP1 Truncating Mutation in a Patient Originally Diagnosed as C Syndrome.

Sci Rep. 2018 Jan 12;8(1):694

Authors: Urreizti R, Damanti S, Esteve C, Franco-Valls H, Castilla-Vallmanya L, Tonda R, Cormand B, Vilageliu L, Opitz JM, Neri G, Grinberg D, Balcells S

Abstract
De novo FOXP1 mutations have been associated with intellectual disability (ID), motor delay, autistic features and a wide spectrum of speech difficulties. C syndrome (Opitz C trigonocephaly syndrome) is a rare and genetically heterogeneous condition, characterized by trigonocephaly, craniofacial anomalies and ID. Several different chromosome deletions and and point mutations in distinct genes have been associated with the disease in patients originally diagnosed as Opitz C. By whole exome sequencing we identified a de novo splicing mutation in FOXP1 in a patient, initially diagnosed as C syndrome, who suffers from syndromic intellectual disability with trigonocephaly. The mutation (c.1428 + 1 G > A) promotes the skipping of exon 16, a frameshift and a premature STOP codon (p.Ala450GLyfs*13), as assessed by a minigene strategy. The patient reported here shares speech difficulties, intellectual disability and autistic features with other FOXP1 syndrome patients, and thus the diagnosis for this patient should be changed. Finally, since trigonocephaly has not been previously reported in FOXP1 syndrome, it remains to be proved whether it may be associated with the FOXP1 mutation.

PMID: 29330474 [PubMed - in process]

Evolution of cytogenetically normal acute myeloid leukemia during therapy and relapse: An exome sequencing study of 50 patients.

Clin Cancer Res. 2018 Jan 12;:

Authors: Greif PA, Hartmann L, Vosberg S, Stief S, Mattes R, Hellmann I, Metzeler KH, Herold T, Bamopoulos S, Kerbs P, Jurinovic V, Schumacher D, Pastore F, Bräundl K, Zellmeier E, Ksienzyk B, Konstandin N, Schneider S, Graf A, Krebs S, Blum H, Neumann M, Baldus C, Bohlander SK, Wolf S, Goerlich D, Berdel WE, Woermann BJ, Hiddemann W, Spiekermann K

Abstract
PURPOSE: To study mechanisms of therapy-resistance and disease progression, we analyzed the evolution of cytogenetically normal acute myeloid leukemia (CN-AML) based on somatic alterations.
EXPERIMENTAL DESIGN: We performed exome-sequencing of matched diagnosis, remission and relapse samples from 50 CN-AML patients treated with intensive chemotherapy. Mutation patterns were correlated with clinical parameters.
RESULTS: Evolutionary patterns correlated with clinical outcome. Gain of mutations was associated with late relapse. Alterations of epigenetic regulators were frequently gained at relapse with recurring alterations of KDM6A constituting a mechanism of cytarabine resistance. Low KDM6A expression correlated with adverse clinical outcome, particularly in male patients. At complete remission, persistent mutations representing pre-leukemic lesions were observed in 48% of patients. The persistence of DNMT3A mutations correlated with shorter time to relapse.
CONCLUSION: Chemotherapy resistance might be acquired through gain of mutations. Insights into the evolution during therapy and disease progression lay the foundation for tailored approaches to treat or prevent relapse of CN-AML.

PMID: 29330206 [PubMed - as supplied by publisher]

Mutations in PI3K110δ cause impaired NK cell function partially rescued by rapamycin treatment.

J Allergy Clin Immunol. 2018 Jan 09;:

Authors: Ruiz-García R, Vargas-Hernandez A, Chinn IK, Angelo LS, Cao TN, Coban-Akdemir Z, Jhangiani SN, Meng Q, Forbes LR, Muzny DM, Allende LM, Ehlayel MS, Gibbs RA, Lupski JR, Uzel G, Orange JS, Mace EM

Abstract
BACKGROUND: Heterozygous gain-of-function mutations in PI3K110 lead to lymphadenopathy, lymphoid hyperplasia, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) viremia, and sinopulmonary infections.
OBJECTIVE: The known role of NK cell function in the control of EBV and CMV prompted us to investigate the functional and phenotypic effect of PI3K110δ mutations on NK cell subsets and cytotoxic function.
METHODS: Patient mutations were identified by whole exome or targeted sequencing. We performed NK cell phenotyping and functional analysis of patient cells by flow cytometry, standard Cr51 cytotoxicity assays, and quantitative confocal microscopy.
RESULTS: PI3K110δ mutations led to an altered NK cell developmental phenotype and cytotoxic dysfunction. Impaired NK cell cytotoxicity was due to decreased conjugate formation with susceptible target cells and abrogated activation of cell machinery required for target cell killing. These defects were partially restored following the initiation of treatment with rapamycin in three patients.
CONCLUSION: We describe novel NK cell functional deficiency due to PI3K110δ mutation, which is a likely contributor to the severe viremia observed in these patients. Rapamycin treatment partially restores NK cell function, providing further rationale for its use in this disease.

PMID: 29330011 [PubMed - as supplied by publisher]

Pipeline to gene discovery - Analysing familial Parkinsonism in the Queensland Parkinson's Project.

Parkinsonism Relat Disord. 2018 Jan 03;:

Authors: Bentley SR, Bortnick S, Guella I, Fowdar JY, Silburn PA, Wood SA, Farrer MJ, Mellick GD

Abstract
INTRODUCTION: Family based study designs provide an informative resource to identify disease-causing mutations. The Queensland Parkinson's Project (QPP) has been involved in numerous genetic screening studies; however, details of the families enrolled into the register have not been comprehensively reported. This article characterises the families enrolled in the QPP and summarises monogenic forms of hereditary Parkinsonism found in the register.
METHOD: The presence of pathogenic point mutations and copy number variations (CNVs) were, generally, screened in a sample of over 1000 PD patients from the total of 1725. Whole exome sequencing (WES) was performed on eighteen probands from multiplex families.
RESULTS: The QPP contains seventeen incidences of confirmed monogenic forms of PD, including LRRK2 p.G2019S, VPS35 p.D620N, SNCA duplications and PARK2 p.G430D (hom) & exon 4 deletion (hom). Of these seventeen, five belong to multi-incident families, while another eight have a family history of at least one other case of PD. In additional families, WES did not identify known forms of monogenic Parkinsonism; however, three heterozygous mutations in PARK2, p.R275W, p.Q34fs, and a 40bp deletion in exon 3 were identified. Of these three mutations, only the 40bp deletion segregated with disease in a dominant inheritance pattern.
CONCLUSION: Eighteen probands have screened negative for known CNVs and mutations that cause clear monogenic forms of PD. Each family is a candidate for further genetic analysis to identify genetic variants segregating with disease. The families enrolled in the QPP provide a useful resource to aid in identifying novel forms of monogenic PD.

PMID: 29329938 [PubMed - as supplied by publisher]

Mutation burden profile in familial Alzheimer's disease cases from India.

Neurobiol Aging. 2017 Dec 12;:

Authors: Syama A, Sen S, Kota LN, Viswanath B, Purushottam M, Varghese M, Jain S, Panicker MM, Mukherjee O

Abstract
This study attempts to identify coding risk variants in genes previously implicated in Alzheimer's disease (AD) pathways, through whole-exome sequencing of subjects (N = 17) with AD, with a positive family history of dementia (familial AD). We attempted to evaluate the mutation burden in genes encoding amyloid precursor protein metabolism and previously linked to risk of dementias. Novel variants were identified in genes involved in amyloid precursor protein metabolism such as PSEN1 (chr 14:73653575, W161C, tgg > tgT), PLAT (chr 8:42039530,G272R), and SORL1 (chr11:121414373,G601D). The mutation burden assessment of dementia-related genes for all 17 cases revealed 45 variants, which were either shared across subjects, or were present in just the 1 patient. The study shows that the clinical characteristics, and genetic correlates, obtained in this sample are broadly comparable to the other studies that have investigated familial forms of AD. Our study identifies rare deleterious genetic variations, in the coding region of genes involved in amyloid signaling, and other dementia-associated pathways.

PMID: 29329714 [PubMed - as supplied by publisher]

19 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 2018/01/13

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.

18 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 2018/01/13

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.

Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes.

Genes (Basel). 2018 Jan 10;9(1):

Authors: Astuti GDN, van den Born LI, Khan MI, Hamel CP, Bocquet B, Manes G, Quinodoz M, Ali M, Toomes C, McKibbin M, El-Asrag ME, Haer-Wigman L, Inglehearn CF, Black GCM, Hoyng CB, Cremers FPM, Roosing S

Abstract
Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs. Homozygosity mapping data was available for five cases. Variants with minor allele frequencies ≤ 0.5% in public databases were selected as candidate disease-causing variants. These variants were ranked based on their: (a) presence in a gene that was previously implicated in IRD; (b) minor allele frequency in the Exome Aggregation Consortium database (ExAC); (c) in silico pathogenicity assessment using the combined annotation dependent depletion (CADD) score; and (d) interaction of the corresponding protein with known IRD-associated proteins. Twelve unique variants were found in 11 different genes in 11 IRD probands. Novel autosomal recessive and dominant inheritance patterns were found for variants in Small Nuclear Ribonucleoprotein U5 Subunit 200 (SNRNP200) and Zinc Finger Protein 513 (ZNF513), respectively. Using our pathogenicity assessment, a variant in DEAH-Box Helicase 32 (DHX32) was the top ranked novel candidate gene to be associated with IRDs, followed by eight medium and lower ranked candidate genes. The identification of candidate disease-associated sequence variants in 11 single families underscores the notion that the previously identified IRD-associated genes collectively carry > 90% of the defects implicated in IRDs. To identify multiple patients or families with variants in the same gene and thereby provide extra proof for pathogenicity, worldwide data sharing is needed.

PMID: 29320387 [PubMed]

Identification of a single MPV17 nonsense-associated altered splice variant in 24 South African infants with mitochondrial neurohepatopathy.

Clin Genet. 2018 Jan 10;:

Authors: Meldau S, De Lacy R, Riordan G, Goddard E, Pillay K, Fieggen K, Marais D, Van der Watt G

Abstract
MPV17-related mitochondrial neurohepatopathy is a rare genetic disorder worldwide. We report on a novel pathogenic variant in the MPV17 gene in 24 unrelated neurohepatopathic infants of non-consanguineous Black South African heritage. Exome sequencing identified homozygosity for a c.106C>T nonsense variant in exon 3 of the human MPV17 gene in two unrelated index patients. mRNA analysis revealed transcripts both with and without exon 3, indicating both reduced splice efficiency and premature termination as mechanisms for disease. Carrier frequency in this population was found to be 1 in 68 (95% CI; 1/122 - 1/38) with an estimated newborn incidence of 1 in 18496 (95% CI; 1/59536 - 1/5776). Affected infants all presented with infantile onset neurohepatopathy with none surviving beyond infancy. This description of a relatively common pathogenic variant underlying a previously uncharacterised severe neurohepatopathy in South Africa will engender increased awareness, earlier diagnosis and possibly improve outcome if preventative or specific therapeutic options can be found.

PMID: 29318572 [PubMed - as supplied by publisher]

Integrated case-control and somatic-germline interaction analyses of melanoma susceptibility genes.

Biochim Biophys Acta. 2018 Jan 06;:

Authors: Yu Y, Hu H, Chen JS, Hu F, Fowler J, Scheet P, Zhao H, Huff CD

Abstract
While a number of genes have been implicated in melanoma susceptibility, the role of protein-coding variation in melanoma development and progression remains underexplored. To better characterize the role of germline coding variation in melanoma, we conducted a whole-exome case-control and somatic-germline interaction study involving 322 skin cutaneous melanoma cases from The Cancer Genome Atlas and 3607 controls of European ancestry. We controlled for cross-platform technological stratification using XPAT and conducted gene-based association tests using VAAST 2. Four established melanoma susceptibility genes achieved nominal statistical significance, MC1R (p = .0014), MITF (p = .0165) BRCA2 (p = .0206), and MTAP (p = .0393). We also observed a suggestive association for FANCA (p = .002), a gene previously implicated in melanoma survival. The association signal for BRCA2 was driven primarily by likely gene disrupting (LGD) variants, with an Odds Ratio (OR) of 5.62 (95% Confidence Interval (CI) 1.03-30.1). In contrast, the association signals for MC1R and MITF were driven primarily by predicted pathogenic non-LGD coding variants, with estimated ORs of 1.4 to 3.0 for MC1R and 4.1 for MITF. MTAP exhibited an excess of both LGD and predicted damaging non-LGD variants among cases, with ORs of 5.62 and 3.72, respectively, although neither category was significant. For individuals with known or predicted damaging variants, age of disease onset was significantly lower for two of the four genes, MC1R (p = .005) and MTAP (p = .035). In an analysis of germline carrier status and overlapping copy number alterations, we observed no evidence to support a two-hit model of carcinogenesis in any of the four genes. Although MC1R carriers were represented proportionally among the four molecular tumor subtypes, these individuals accounted for 69% of ultraviolet (UV) radiation mutational signatures among triple-wild type tumors (p = .040), highlighting the increased sensitivity to UV exposure among individuals with loss-of-function variants in MC1R.

PMID: 29317335 [PubMed - as supplied by publisher]

PSEN1 p.Met233Val in a Complex Neurodegenerative Movement and Neuropsychiatric Disorder.

J Mov Disord. 2018 Jan 11;:

Authors: Appel-Cresswell S, Guella I, Lehman A, Foti D, Farrer MJ

Abstract
Mutations in presenilin 1 (PSEN1) are the most common cause of autosomal dominant Alzheimer's disease. Here, we report a Canadian-Vietnamese family carrying a PSEN1 p.Met233Val mutation with an exceptionally early and severe presentation that includes a wide range of atypical symptoms, including prominent ataxia, Parkinsonism, spasticity, dystonia, action tremor, myoclonus, bulbar symptoms, seizures, hallucinations and behavioral changes. Whole-exome sequencing (WES) was performed on the affected proband after many assessments over several years proved diagnostically inconclusive. The results were analyzed using the AnnEx "Annotated Exomes" browser (http://annex.can.ubc.ca), a web-based platform that facilitates WES variant annotation and interpretation. High-throughput sequencing can be especially informative for complex neurological disorders, and WES warrants consideration as a first-line clinical test. Data analyses facilitated by web-based bioinformatics tools have great potential for novel insight, although confirmatory, diagnostically accredited Sanger sequencing is recommended prior to reporting.

PMID: 29316780 [PubMed - as supplied by publisher]

Precision Medicine in Children and Young Adults with Hematologic Malignancies and Blood Disorders: The Columbia University Experience.

Front Pediatr. 2017;5:265

Authors: Marks LJ, Oberg JA, Pendrick D, Sireci AN, Glasser C, Coval C, Zylber RJ, Chung WK, Pang J, Turk AT, Hsiao SJ, Mansukhani MM, Glade Bender JL, Kung AL, Sulis ML

Abstract
Background: The advent of comprehensive genomic profiling has markedly advanced the understanding of the biology of pediatric hematological malignancies, however, its application to clinical care is still unclear. We present our experience integrating genomic data into the clinical management of children with high-risk hematologic malignancies and blood disorders and describe the broad impact that genomic profiling has in multiple aspects of patient care.
Methods: The Precision in Pediatric Sequencing Program at Columbia University Medical Center instituted prospective clinical next-generation sequencing (NGS) for high-risk malignancies and blood disorders. Testing included cancer whole exome sequencing (WES) of matched tumor-normal samples or targeted sequencing of 467 cancer-associated genes, when sample adequacy was a concern, and tumor transcriptome (RNA-seq). A multidisciplinary molecular tumor board conducted interpretation of results and final tiered reports were transmitted to the electronic medical record according to patient preferences.
Results: Sixty-nine samples from 56 patients with high-risk hematologic malignancies and blood disorders were sequenced. Patients carried diagnoses of myeloid malignancy (n = 25), lymphoid malignancy (n = 25), or histiocytic disorder (n = 6). Six patients had only constitutional WES, performed for a suspicion of an inherited predisposition for their disease. For the remaining 50 patients, tumor was sequenced with matched normal tissue when available. The mean number of somatic variants per sample was low across the different disease categories (2.85 variants/sample). Interestingly, a gene fusion was identified by RNA-seq in 58% of samples who had adequate RNA available for testing. Molecular profiling of tumor tissue led to clinically impactful findings in 90% of patients. Forty patients (80%) had at least one targetable gene variant or fusion identified in their tumor tissue; however, only seven received targeted therapy. Importantly, NGS findings contributed to the refinement of diagnosis and prognosis for 34% of patients. Known or likely pathogenic germline alterations were discovered in 24% of patients involving cancer predisposition genes in 12% of cases.
Conclusion: Incorporating whole exome and transcriptome profiling of tumor and normal tissue into clinical practice is feasible, and the value that comprehensive testing provides extends beyond the ability to target-specific mutations.

PMID: 29312904 [PubMed]

Two Brothers with Atypical UNC13D-Related Hemophagocytic Lymphohistiocytosis Characterized by Massive Lung and Brain Involvement.

Front Immunol. 2017;8:1892

Authors: Giardino G, De Luca M, Cirillo E, Palma P, Romano R, Valeriani M, Papetti L, Saunders C, Cancrini C, Pignata C

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory condition. Variants in different genes have been associated with the familial forms of the syndrome (FHL), usually presenting within the first 2 years of life. Due to increasing awareness of the signs and symptoms of HLH and a better understanding of the genetic basis of the disease, FHL has been increasingly diagnosed in patients presenting beyond infancy. Here, we report on two brothers with atypical, late-onset HLH in which whole exome sequencing revealed a homozygous pathogenic UNC13D variant. In the first brother, the clinical phenotype was dominated by a massive lung involvement. In the second brother a progressive neurological deterioration was observed. In both cases, the clinical manifestations at symptom onset were misleading, making the diagnosis difficult to achieve. This report expands the spectrum of clinical presentations of FLH3. Moreover, it highlights the importance to warn clinicians to keep a high level of suspicion in patients presenting with fever, cytopenia, splenomegaly of unknown origin, and unresponsiveness to conventional treatment even beyond early childhood. Moreover, this report emphasizes that insidious neurologic symptoms may represent the initial or sole presenting sign of FHL, even in the absence of peripheral signs of activation.

PMID: 29312353 [PubMed]

Early detection and evolution of pre-leukemic clones in therapy-related myeloid neoplasms following autologous SCT.

Blood. 2018 Jan 08;:

Authors: Berger G, Kroeze LI, Koorenhof-Scheele TN, de Graaf AO, Yoshida K, Ueno H, Shiraishi Y, Miyano S, van den Berg E, Schepers H, van der Reijden BA, Ogawa S, Vellenga E, Jansen JH

Abstract
Therapy-related myeloid neoplasms (tMNs) are severe adverse events that can occur following treatment with autologous hematopoietic stem cell transplantation (ASCT). This study aimed to investigate the development of tMN following ASCT at the molecular level by whole exome sequencing (WES) and targeted deep sequencing (TDS) in sequential (pre-) tMN samples. WES identified a significantly higher number of mutations in tMN as compared to de novo MDS (median 27 vs 12, p=0.001). The mutations found in tMN did not carry a clear ageing-signature, unlike the mutations found in de novo MDS, indicating a different mutational mechanism. In some patients, tMN mutations were identified in both myeloid and T-cells, suggesting that tMNs may originate from early hematopoietic stem cells (HSCs). However, the mutational spectra of tMN and the preceding malignancies did not overlap, excluding common ancestry for these malignancies. Using TDS, tMN mutations were identified at low variant allele frequencies (VAFs) in transplant material in 70% of the tMN cases. Reconstruction of clonal patterns based on VAFs, revealed that pre-malignant clones can be present more than seven years preceding tMN diagnosis, a finding that was confirmed by immunohistochemistry on bone marrow biopsies. Our results indicate that tMN development following ASCT originates in HSCs bearing tMN mutations that are present years before disease onset and that post-ASCT treatment can influence the selection of these clones. Early detection of pre-malignant clones and monitoring their evolutionary trajectory may help to predict the development of tMN and guide early intervention in the future.

PMID: 29311096 [PubMed - as supplied by publisher]

An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio.

Nat Commun. 2017 09 19;8(1):601

Authors: Sadybekov A, Tian C, Arnesano C, Katritch V, Herring BE

Abstract
The Rho guanine nucleotide exchange factor (RhoGEF) Trio promotes actin polymerization by directly activating the small GTPase Rac1. Recent studies suggest that autism spectrum disorder (ASD)-related behavioral phenotypes in animal models of ASD can be produced by dysregulation of Rac1's control of actin polymerization at glutamatergic synapses. Here, in humans, we discover a large cluster of ASD-related de novo mutations in Trio's Rac1 activating domain, GEF1. Our study reveals that these mutations produce either hypofunctional or hyperfunctional forms of Trio in rodent neurons in vitro. In accordance with pathological increases or decreases in glutamatergic neurotransmission observed in animal models of ASD, we find that these mutations result in either reduced synaptic AMPA receptor expression or enhanced glutamatergic synaptogenesis. Together, our findings implicate both excessive and reduced Trio activity and the resulting synaptic dysfunction in ASD-related pathogenesis, and point to the Trio-Rac1 pathway at glutamatergic synapses as a possible key point of convergence of many ASD-related genes.Trio is a RhoGEF protein that promotes actin polymerization and is implicated in the regulation of glutamatergic synapses in autism spectrum disorder (ASD). Here the authors identify a large cluster of de novo mutations in the GEF1 domain of Trio in whole-exome sequencing data from individuals with ASD, and confirm that some of these mutations lead to glutamatergic dysregulation in vitro.

PMID: 28928363 [PubMed - indexed for MEDLINE]

Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes-Brocks Syndrome.

Hum Mutat. 2017 Apr;38(4):373-377

Authors: Webb BD, Metikala S, Wheeler PG, Sherpa MD, Houten SM, Horb ME, Schadt EE

Abstract
A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 (DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies. The DACT1 c.1256G>A;p.Trp419* variant segregated appropriately in the family consistent with an autosomal dominant mode of inheritance. DACT1 is a member of the Wnt-signaling pathway, and mice homozygous for null alleles display multiple congenital anomalies including absent anus with blind-ending colon and genitourinary malformations. To investigate the DACT1 c.1256G>A variant, HEK293 cells were transfected with mutant DACT1 cDNA plasmid, and immunoblotting revealed stability of the DACT1 p.Trp419* protein. Overexpression of DACT1 c.1256G>A mRNA in Xenopus embryos revealed a specific gastrointestinal phenotype of enlargement of the proctodeum. Together, these findings suggest that the DACT1 c.1256G>A nonsense variant is causative of a specific genetic syndrome with features overlapping Townes-Brocks syndrome.

PMID: 28054444 [PubMed - indexed for MEDLINE]

Bi-allelic IARS mutations in a child with intra-uterine growth retardation, neonatal cholestasis, and mild developmental delay.

Clin Genet. 2017 Jun;91(6):913-917

Authors: Orenstein N, Weiss K, Oprescu SN, Shapira R, Kidron D, Vanagaite-Basel L, Antonellis A, Muenke M

Abstract
Recently, bi-allelic mutations in cytosolic isoleucyl-tRNA synthetase (IARS) have been described in three individuals with growth delay, hepatic dysfunction, and neurodevelopmental disabilities. Here we report an additional subject with this condition identified by whole-exome sequencing. Our findings support the association between this disorder and neonatal cholestasis with distinct liver pathology. Furthermore, we provide functional data on two novel missense substitutions and expand the phenotype to include mild developmental delay, skin hyper-elasticity, and hypervitaminosis D.

PMID: 27891590 [PubMed - indexed for MEDLINE]

Next-generation sequencing in neuromuscular diseases.

Curr Opin Neurol. 2016 10;29(5):527-36

Authors: Efthymiou S, Manole A, Houlden H

Abstract
PURPOSE OF REVIEW: Neuromuscular diseases are clinically and genetically heterogeneous and probably contain the greatest proportion of causative Mendelian defects than any other group of conditions. These disorders affect muscle and/or nerves with neonatal, childhood or adulthood onset, with significant disability and early mortality. Along with heterogeneity, unidentified and often very large genes require complementary and comprehensive methods in routine molecular diagnosis. Inevitably, this leads to increased diagnostic delays and challenges in the interpretation of genetic variants.
RECENT FINDINGS: The application of next-generation sequencing, as a research and diagnostic strategy, has made significant progress into solving many of these problems. The analysis of these data is by no means simple, and the clinical input is essential to interpret results.
SUMMARY: In this review, we describe using examples the recent advances in the genetic diagnosis of neuromuscular disorders, in research and clinical practice and the latest developments that are underway in next-generation sequencing. We also discuss the latest collaborative initiatives such as the Genomics England (Department of Health, UK) genome sequencing project that combine rare disease clinical phenotyping with genomics, with the aim of defining the vast majority of rare disease genes in patients as well as modifying risks and pharmacogenomics factors.

PMID: 27588584 [PubMed - indexed for MEDLINE]

Utility of Population-Level DNA Sequence Data in the Diagnosis of Hereditary Endocrine Disease.

J Endocr Soc. 2017 Dec 01;1(12):1507-1526

Authors: Newey PJ, Berg JN, Zhou K, Palmer CNA, Thakker RV

Abstract
Context: Genetic testing is increasingly used for clinical diagnosis, although variant interpretation presents a major challenge because of high background rates of rare coding-region variation, which may contribute to inaccurate estimates of variant pathogenicity and disease penetrance.
Objective: To use the Exome Aggregation Consortium (ExAC) data set to determine the background population frequencies of rare germline coding-region variants in genes associated with hereditary endocrine disease and to evaluate the clinical utility of these data.
Design Setting Participants: Cumulative frequencies of rare nonsynonymous single-nucleotide variants were established for 38 endocrine disease genes in 60,706 unrelated control individuals. The utility of gene-level and variant-level metrics of tolerability was assessed, and the pathogenicity and penetrance of germline variants previously associated with endocrine disease evaluated.
Results: The frequency of rare coding-region variants differed markedly between genes and was correlated with the degree of evolutionary conservation. Genes associated with dominant monogenic endocrine disorders typically harbored fewer rare missense and/or loss-of-function variants than expected. In silico variant prediction tools demonstrated low clinical specificity. The frequency of several endocrine disease‒associated variants in the ExAC cohort far exceeded estimates of disease prevalence, indicating either misclassification or overestimation of disease penetrance. Finally, we illustrate how rare variant frequencies may be used to anticipate expected rates of background rare variation when performing disease-targeted genetic testing.
Conclusions: Quantifying the frequency and spectrum of rare variation using population-level sequence data facilitates improved estimates of variant pathogenicity and penetrance and should be incorporated into the clinical decision-making algorithm when undertaking genetic testing.

PMID: 29308445 [PubMed]