GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome.

Am J Hum Genet. 2017 May 04;100(5):831-836

Authors: Patel N, Shamseldin HE, Sakati N, Khan AO, Softa A, Al-Fadhli FM, Hashem M, Abdulwahab FM, Alshidi T, Alomar R, Alobeid E, Wakil SM, Colak D, Alkuraya FS

Abstract
Larsen syndrome is characterized by the dislocation of large joints and other less consistent clinical findings. Heterozygous FLNB mutations account for the majority of Larsen syndrome cases, but biallelic mutations in CHST3 and B4GALT7 have been more recently described, thus confirming the existence of recessive forms of the disease. In a multiplex consanguineous Saudi family affected by severe and recurrent large joint dislocation and severe myopia, we identified a homozygous truncating variant in GZF1 through a combined autozygome and exome approach. Independently, the same approach identified a second homozygous truncating GZF1 variant in another multiplex consanguineous family affected by severe myopia, retinal detachment, and milder skeletal involvement. GZF1 encodes GDNF-inducible zinc finger protein 1, a transcription factor of unknown developmental function, which we found to be expressed in the eyes and limbs of developing mice. Global transcriptional profiling of cells from affected individuals revealed a shared pattern of gene dysregulation and significant enrichment of genes encoding matrix proteins, including P3H2, which hints at a potential disease mechanism. Our results suggest that GZF1 mutations cause a phenotype of severe myopia and significant articular involvement not previously described in Larsen syndrome.

PMID: 28475863 [PubMed - in process]

A cumulative effect involving malfunction of the PTH1R and ATP4A genes explains a familial gastric neuroendocrine tumor with hypothyroidism and arthritis.

Gastric Cancer. 2017 May 04;:

Authors: Calvete O, Herraiz M, Reyes J, Patiño A, Benitez J

Abstract
BACKGROUND: Type I gastric neuroendocrine tumors (gNETs) classically arise because of hypergastrinemia and involve destruction of parietal cells, which are responsible for gastric acid secretion through the ATP4A proton pump and for intrinsic factor production.
METHODS: By whole exome sequencing, we studied a family with three members with gNETs plus hypothyroidism and rheumatoid arthritis to uncover their genetic origin.
RESULTS: A heterozygous missense mutation in the ATP4A gene was identified. Carriers of this variant had low ferritin and vitamin B12 levels but did not develop gNETs. A second heterozygous mutation was also uncovered (PTH1R p.E546K). Carriers exhibited hypothyroidism and one of them had rheumatoid arthritis. Gastrin activates parathyroid hormone like hormone/parathyroid hormone 1 receptor (PTH1R) signaling, which is involved in gastric cell homeostasis. Activation of parathyroid hormone/PTH1R, which is upregulated by thyrotropin in the thyroid, is also involved in RANKL expression, which regulates bone homeostasis. Thyrotropin and RANKL expression were deregulated in PTH1R mutation carriers, suggesting a link between the PTH1R gene, hypothyroidism, rheumatoid arthritis, and gastric disease. Only patients with both mutations developed gNETs plus hypothyroidism and rheumatoid arthritis.
CONCLUSION: Both mutations suggest that a collaborative mechanism is operative in this family, in which mutations in these genes affect the function and viability of parietal cells and lead to the achlorhydria that drives hypergastrinemia and the formation of gNETs.

PMID: 28474257 [PubMed - as supplied by publisher]

Use of Clinical Exome Sequencing in Isolated Congenital Heart Disease.

Circ Cardiovasc Genet. 2017 Jun;10(3):

Authors: Zahavich L, Bowdin S, Mital S

PMID: 28473349 [PubMed - in process]

A Case Report of Hypoglycemia and Hypogammaglobulinemia: DAVID syndrome in a patient with a novel NFKB2 mutation.

J Clin Endocrinol Metab. 2017 May 03;:

Authors: Lal RA, Bachrach LK, Hoffman AR, Inlora J, Rego S, Snyder MP, Lewis DB

Abstract
Context: DAVID syndrome (Deficient Anterior pituitary with Variable Immune Deficiency) is a rare disorder in which children present with symptomatic ACTH deficiency preceded by hypogammaglobulinemia from B-cell dysfunction with recurrent infections, termed common variable immunodeficiency (CVID). Subsequent whole exome sequencing studies have revealed germline heterozygous C-terminal mutations of NFKB2 as either a cause of DAVID syndrome or of CVID without clinical hypopituitarism. However, to the best of our knowledge there have been no cases in which the endocrinopathy has presented in the absence of a prior clinical history of CVID.
Case Description: A previously healthy 7 year-old boy with no history of clinical immunodeficiency, presented with profound hypoglycemia and seizures. He was found to have secondary adrenal insufficiency and was started on glucocorticoid replacement. An evaluation for autoimmune disease, including for anti-pituitary antibodies, was negative. Evaluation unexpectedly revealed hypogammaglobulinemia (decreased IgG, IgM, and IgA). He had moderately reduced serotype-specific IgG responses following pneumococcal polysaccharide vaccine. Subsequently, he was found to have growth hormone (GH) deficiency. Six years after initial presentation, whole exome sequencing revealed a novel de novo heterozygous NFKB2 missense mutation c.2596A>C (p.Ser866Arg) in the C-terminal region predicted to abrogate the processing of the p100 NFKB2 protein to its active p52 form.
Conclusions: Isolated early-onset ACTH deficiency is rare and C-terminal region NFKB2 mutations should be considered as an etiology even in the absence of a clinical history of CVID. Early immunologic evaluation is indicated in the diagnosis and management of isolated ACTH deficiency.

PMID: 28472507 [PubMed - as supplied by publisher]

Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing.

Genet Med. 2017 May 04;:

Authors: Haggerty CM, James CA, Calkins H, Tichnell C, Leader JB, Hartzel DN, Nevius CD, Pendergrass SA, Person TN, Schwartz M, Ritchie MD, Carey DJ, Ledbetter DH, Williams MS, Dewey FE, Lopez A, Penn J, Overton JD, Reid JG, Lebo M, Mason-Suares H, Austin-Tse C, Rehm HL, Delisle BP, Makowski DJ, Mehra VC, Murray MF, Fornwalt BK

Abstract
PurposeArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease. Clinical follow-up of incidental findings in ARVC-associated genes is recommended. We aimed to determine the prevalence of disease thus ascertained.MethodsIndividuals (n = 30,716) underwent exome sequencing. Variants in PKP2, DSG2, DSC2, DSP, JUP, TMEM43, or TGFβ3 that were database-listed as pathogenic or likely pathogenic were identified and evidence-reviewed. For subjects with putative loss-of-function (pLOF) variants or variants of uncertain significance (VUS), electronic health records (EHR) were reviewed for ARVC diagnosis, diagnostic criteria, and International Classification of Diseases (ICD-9) codes.ResultsEighteen subjects had pLOF variants; none of these had an EHR diagnosis of ARVC. Of 14 patients with an electrocardiogram, one had a minor diagnostic criterion; the rest were normal. A total of 184 subjects had VUS, none of whom had an ARVC diagnosis. The proportion of subjects with VUS with major (4%) or minor (13%) electrocardiogram diagnostic criteria did not differ from that of variant-negative controls. ICD-9 codes showed no difference in defibrillator use, electrophysiologic abnormalities or nonischemic cardiomyopathies in patients with pLOF or VUSs compared with controls.ConclusionpLOF variants in an unselected cohort were not associated with ARVC phenotypes based on EHR review. The negative predictive value of EHR review remains uncertain.GENETICS in MEDICINE advance online publication, 4 May 2017; doi:10.1038/gim.2017.40.

PMID: 28471438 [PubMed - as supplied by publisher]

Assessment of the ExAC data set for the presence of individuals with pathogenic genotypes implicated in severe Mendelian pediatric disorders.

Genet Med. 2017 May 04;:

Authors: Tarailo-Graovac M, Zhu JYA, Matthews A, van Karnebeek CDM, Wasserman WW

Abstract
PurposeWe analyzed the Exome Aggregation Consortium (ExAC) data set for the presence of individuals with pathogenic genotypes implicated in Mendelian pediatric disorders.MethodsClinVar likely/pathogenic variants supported by at least one peer-reviewed publication were assessed within the ExAC database to identify individuals expected to exhibit a childhood disorder based on concordance with disease inheritance modes: heterozygous (for dominant), homozygous (for recessive) or hemizygous (for X-linked recessive conditions). Variants from 924 genes reported to cause Mendelian childhood disorders were considered.ResultsWe identified ExAC individuals with candidate pathogenic genotypes for 190 previously published likely/pathogenic variants in 128 genes. After curation, we determined that 113 of the variants have sufficient support for pathogenicity and identified 1,717 ExAC individuals (~2.8% of the ExAC population) with corresponding possible/disease-associated genotypes implicated in rare Mendelian disorders, ranging from mild (e.g., due to SCN2A deficiency) to severe pediatric conditions (e.g., due to FGFR1 deficiency).ConclusionLarge-scale sequencing projects and data aggregation consortia provide unprecedented opportunities to determine the prevalence of pathogenic genotypes in unselected populations. This knowledge is crucial for understanding the penetrance of disease-associated variants, phenotypic variability, somatic mosaicism, as well as published literature curation for variant classification procedures and predicted clinical outcomes.GENETICS in MEDICINE advance online publication, 4 May 2017; doi:10.1038/gim.2017.50.

PMID: 28471432 [PubMed - as supplied by publisher]

Systematic Cell-Based Phenotyping of Missense Alleles.

Methods Mol Biol. 2017;1601:215-228

Authors: Thormählen AS, Runz H

Abstract
Sequencing of the protein-coding genome, the exome, has proven powerful to unravel links between genetic variation and disease for both Mendelian and complex conditions. Importantly, however, the increasing number of sequenced human exomes and mapping of disease-associated alleles is accompanied by a simultaneous, yet exponential increase in the overall number of rare and low frequency alleles identified. For most of these novel alleles, biological consequences remain unknown since reliable experimental approaches to better characterize their impact on protein function are only slowly emerging.Here we review a scalable, cell-based strategy that we have recently established to systematically profile the biological impact of rare and low frequency missense variants in vitro. By applying this approach to missense alleles identified through cohort-level exome sequencing in the low-density lipoprotein receptor (LDLR) we are able to distinguish rare alleles that predispose to familial hypercholesterolemia and myocardial infarction from alleles without obvious impact on LDLR levels or functions. We propose that systematic implementation of such and similar strategies will significantly advance our understanding of the protein-coding human genome and how rare and low frequency genetic variation impacts on health and disease.

PMID: 28470529 [PubMed - in process]

A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula.

Sci Rep. 2017 May 03;7(1):1411

Authors: Khan AO, Becirovic E, Betz C, Neuhaus C, Altmüller J, Maria Riedmayr L, Motameny S, Nürnberg G, Nürnberg P, Bolz HJ

Abstract
Deafblindness is mostly due to Usher syndrome caused by recessive mutations in the known genes. Mutation-negative patients therefore either have distinct diseases, mutations in yet unknown Usher genes or in extra-exonic parts of the known genes - to date a largely unexplored possibility. In a consanguineous Saudi family segregating Usher syndrome type 1 (USH1), NGS of genes for Usher syndrome, deafness and retinal dystrophy and subsequent whole-exome sequencing each failed to identify a mutation. Genome-wide linkage analysis revealed two small candidate regions on chromosome 3, one containing the USH3A gene CLRN1, which has never been associated with Usher syndrome in Saudi Arabia. Whole-genome sequencing (WGS) identified a homozygous deep intronic mutation, c.254-649T > G, predicted to generate a novel donor splice site. CLRN1 minigene-based analysis confirmed the splicing of an aberrant exon due to usage of this novel motif, resulting in a frameshift and a premature termination codon. We identified this mutation in an additional two of seven unrelated mutation-negative Saudi USH1 patients. Locus-specific markers indicated that c.254-649T > G CLRN1 represents a founder allele that may significantly contribute to deafblindness in this population. Our finding underlines the potential of WGS to uncover atypically localized, hidden mutations in patients who lack exonic mutations in the known disease genes.

PMID: 28469144 [PubMed - in process]

Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis.

Sci Transl Med. 2017 May 03;9(388):

Authors: Smith BN, Topp SD, Fallini C, Shibata H, Chen HJ, Troakes C, King A, Ticozzi N, Kenna KP, Soragia-Gkazi A, Miller JW, Sato A, Dias DM, Jeon M, Vance C, Wong CH, de Majo M, Kattuah W, Mitchell JC, Scotter EL, Parkin NW, Sapp PC, Nolan M, Nestor PJ, Simpson M, Weale M, Lek M, Baas F, Vianney de Jong JM, Ten Asbroek ALMA, Redondo AG, Esteban-Pérez J, Tiloca C, Verde F, Duga S, Leigh N, Pall H, Morrison KE, Al-Chalabi A, Shaw PJ, Kirby J, Turner MR, Talbot K, Hardiman O, Glass JD, De Belleroche J, Maki M, Moss SE, Miller C, Gellera C, Ratti A, Al-Sarraj S, Brown RH, Silani V, Landers JE, Shaw CE

Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the ANXA11 gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases (P = 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11-positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p.D40G mutation. Transfected human embryonic kidney cells expressing ANXA11 with the p.D40G mutation and other N-terminal mutations showed altered binding to calcyclin, and the p.R235Q mutant protein formed insoluble aggregates. We conclude that mutations in ANXA11 are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis.

PMID: 28469040 [PubMed - in process]

A case report of novel mutation in PRF1 gene, which causes familial autosomal recessive hemophagocytic lymphohistiocytosis.

BMC Med Genet. 2017 May 03;18(1):49

Authors: Bordbar MR, Modarresi F, Farazi Fard MA, Dastsooz H, Shakib Azad N, Faghihi MA

Abstract
BACKGROUND: Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening immunodeficiency and multi-organ disease that affects people of all ages and ethnic groups. Common symptoms and signs of this disease are high fever, hepatosplenomegaly, and cytopenias. Familial form of HLH disease, which is an autosomal recessive hematological disorder is due to disease-causing mutations in several genes essential for NK and T-cell granule-mediated cytotoxic function. For an effective cytotoxic response from cytotoxic T lymphocyte or NK cell encountering an infected cell or tumor cell, different processes are required, including trafficking, docking, priming, membrane fusion, and entry of cytotoxic granules into the target cell leading to apoptosis. Therefore, genes involved in these steps play important roles in the pathogenesis of HLH disease which include PRF1, UNC13D (MUNC13-4), STX11, and STXBP2 (MUNC18-2).
CASE PRESENTATION: Here, we report a novel missense mutation in an 8-year-old boy suffered from hepatosplenomegaly, hepatitis, epilepsy and pancytopenia. The patient was born to a first-cousin parents with no previous documented disease in his parents. To identify mutated gene in the proband, Whole Exome Sequencing (WES) utilizing next generation sequencing was used on an Illumina HiSeq 2000 platform on DNA sample from the patient. Results showed a novel deleterious homozygous missense mutation in PRF1 gene (NM_001083116: exon3: c. 1120 T > G, p.W374G) in the patient and then using Sanger sequencing it was confirmed in the proband and his parents. Since his parents were heterozygous for the identified mutation, autosomal recessive pattern of inheritance was confirmed in the family.
CONCLUSIONS: Our study identified a rare new pathogenic missense mutation in PRF1 gene in patient with HLH disease and it is the first report of mutation in PRF1 in Iranian patients with this disease.

PMID: 28468610 [PubMed - in process]

Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome.

Am J Hum Genet. 2017 Feb 02;100(2):281-296

Authors: Oud MM, Tuijnenburg P, Hempel M, van Vlies N, Ren Z, Ferdinandusse S, Jansen MH, Santer R, Johannsen J, Bacchelli C, Alders M, Li R, Davies R, Dupuis L, Cale CM, Wanders RJ, Pals ST, Ocaka L, James C, Müller I, Lehmberg K, Strom T, Engels H, Williams HJ, Beales P, Roepman R, Dias P, Brunner HG, Cobben JM, Hall C, Hartley T, Le Quesne Stabej P, Mendoza-Londono R, Davies EG, de Sousa SB, Lessel D, Arts HH, Kuijpers TW

Abstract
EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities.

PMID: 28132690 [PubMed - indexed for MEDLINE]

Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability.

Am J Hum Genet. 2017 Feb 02;100(2):257-266

Authors: Anikster Y, Haack TB, Vilboux T, Pode-Shakked B, Thöny B, Shen N, Guarani V, Meissner T, Mayatepek E, Trefz FK, Marek-Yagel D, Martinez A, Huttlin EL, Paulo JA, Berutti R, Benoist JF, Imbard A, Dorboz I, Heimer G, Landau Y, Ziv-Strasser L, Malicdan MC, Gemperle-Britschgi C, Cremer K, Engels H, Meili D, Keller I, Bruggmann R, Strom TM, Meitinger T, Mullikin JC, Schwartz G, Ben-Zeev B, Gahl WA, Harper JW, Blau N, Hoffmann GF, Prokisch H, Opladen T, Schiff M

Abstract
Phenylketonuria (PKU, phenylalanine hydroxylase deficiency), an inborn error of metabolism, can be detected through newborn screening for hyperphenylalaninemia (HPA). Most individuals with HPA harbor mutations in the gene encoding phenylalanine hydroxylase (PAH), and a small proportion (2%) exhibit tetrahydrobiopterin (BH4) deficiency with additional neurotransmitter (dopamine and serotonin) deficiency. Here we report six individuals from four unrelated families with HPA who exhibited progressive neurodevelopmental delay, dystonia, and a unique profile of neurotransmitter deficiencies without mutations in PAH or BH4 metabolism disorder-related genes. In these six affected individuals, whole-exome sequencing (WES) identified biallelic mutations in DNAJC12, which encodes a heat shock co-chaperone family member that interacts with phenylalanine, tyrosine, and tryptophan hydroxylases catalyzing the BH4-activated conversion of phenylalanine into tyrosine, tyrosine into L-dopa (the precursor of dopamine), and tryptophan into 5-hydroxytryptophan (the precursor of serotonin), respectively. DNAJC12 was undetectable in fibroblasts from the individuals with null mutations. PAH enzyme activity was reduced in the presence of DNAJC12 mutations. Early treatment with BH4 and/or neurotransmitter precursors had dramatic beneficial effects and resulted in the prevention of neurodevelopmental delay in the one individual treated before symptom onset. Thus, DNAJC12 deficiency is a preventable and treatable cause of intellectual disability that should be considered in the early differential diagnosis when screening results are positive for HPA. Sequencing of DNAJC12 may resolve any uncertainty and should be considered in all children with unresolved HPA.

PMID: 28132689 [PubMed - indexed for MEDLINE]

12 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 2017/05/04

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.

IFT81 as a Candidate Gene for Nonsyndromic Retinal Degeneration.

Invest Ophthalmol Vis Sci. 2017 May 01;58(5):2483-2490

Authors: Dharmat R, Liu W, Ge Z, Sun Z, Yang L, Li Y, Wang K, Thomas K, Sui R, Chen R

Abstract
Purpose: IFT81, a core component of the IFT-B complex, involved in the bidirectional transport of ciliary proteins, has been recently implicated in syndromic ciliopathies. However, none of the IFT-B core complex proteins have been associated with nonsyndromic retinal dystrophies. Given the importance of ciliary transport in photoreceptor function and structural maintenance, we sought to investigate the impact of IFT (intraflagellar transport) mutations in nonsyndromic retinopathies.
Methods: Whole exome sequencing was performed on 50 cone-rod dystrophy (CRD) patients that were previously screened for mutations in known retinal disease genes. The impact of candidate mutation was studied using in vitro cell system and in vivo zebrafish assay to determine the pathogenicity of the variant.
Results: Compound heterozygous mutations in IFT81, including one nonsense (c.1213C>T, p.R405*) and one missense variant (c.1841T>C, p.L614P), were identified in a nonsyndromic CRD proband. Extensive functional analyses of the missense variant in cell culture and zebrafish strongly suggests its pathogenic nature. Loss of IFT81 impairs ciliogenesis and, interestingly, the missense variant displayed significantly reduced rescue of ciliogenesis in the IFT81 knockdown in vitro system. Consistently, dramatic reduction of rescue efficiency of the ift81 mutant zebrafish embryo by mRNA with the missense variant was observed, further supporting its pathogenicity.
Conclusions: Consistent with the function of the IFT-B complex in the maintenance of photoreceptor cilium, we report a case of mutations in a core IFT-B protein, IFT81. This represents the first report of mutations in IFT81 as a candidate gene for nonsyndromic retinal dystrophy, hence expanding the phenotype spectrum of IFT-B components.

PMID: 28460050 [PubMed - in process]

Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia.

Brain. 2017 Apr 27;:

Authors: Minnerop M, Kurzwelly D, Wagner H, Soehn AS, Reichbauer J, Tao F, Rattay TW, Peitz M, Rehbach K, Giorgetti A, Pyle A, Thiele H, Altmüller J, Timmann D, Karaca I, Lennarz M, Baets J, Hengel H, Synofzik M, Atasu B, Feely S, Kennerson M, Stendel C, Lindig T, Gonzalez MA, Stirnberg R, Sturm M, Roeske S, Jung J, Bauer P, Lohmann E, Herms S, Heilmann-Heimbach S, Nicholson G, Mahanjah M, Sharkia R, Carloni P, Brüstle O, Klopstock T, Mathews KD, Shy ME, de Jonghe P, Chinnery PF, Horvath R, Kohlhase J, Schmitt I, Wolf M, Greschus S, Amunts K, Maier W, Schöls L, Nürnberg P, Zuchner S, Klockgether T, Ramirez A, Schüle R

Abstract
Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

PMID: 28459997 [PubMed - as supplied by publisher]

Novel candidate genes may be possible predisposing factors revealed by whole exome sequencing in familial esophageal squamous cell carcinoma.

Tumour Biol. 2017 May;39(5):1010428317699115

Authors: Forouzanfar N, Baranova A, Milanizadeh S, Heravi-Moussavi A, Jebelli A, Abbaszadegan MR

Abstract
Esophageal squamous cell carcinoma is one of the deadliest of all the cancers. Its metastatic properties portend poor prognosis and high rate of recurrence. A more advanced method to identify new molecular biomarkers predicting disease prognosis can be whole exome sequencing. Here, we report the most effective genetic variants of the Notch signaling pathway in esophageal squamous cell carcinoma susceptibility by whole exome sequencing. We analyzed nine probands in unrelated familial esophageal squamous cell carcinoma pedigrees to identify candidate genes. Genomic DNA was extracted and whole exome sequencing performed to generate information about genetic variants in the coding regions. Bioinformatics software applications were utilized to exploit statistical algorithms to demonstrate protein structure and variants conservation. Polymorphic regions were excluded by false-positive investigations. Gene-gene interactions were analyzed for Notch signaling pathway candidates. We identified novel and damaging variants of the Notch signaling pathway through extensive pathway-oriented filtering and functional predictions, which led to the study of 27 candidate novel mutations in all nine patients. Detection of the trinucleotide repeat containing 6B gene mutation (a slice site alteration) in five of the nine probands, but not in any of the healthy samples, suggested that it may be a susceptibility factor for familial esophageal squamous cell carcinoma. Noticeably, 8 of 27 novel candidate gene mutations (e.g. epidermal growth factor, signal transducer and activator of transcription 3, MET) act in a cascade leading to cell survival and proliferation. Our results suggest that the trinucleotide repeat containing 6B mutation may be a candidate predisposing gene in esophageal squamous cell carcinoma. In addition, some of the Notch signaling pathway genetic mutations may act as key contributors to esophageal squamous cell carcinoma.

PMID: 28459198 [PubMed - in process]

Whole exome sequencing of sporadic patients with Currarino Syndrome: A report of three trios.

Gene. 2017 Apr 26;:

Authors: Holm I, Spildrejorde M, Stadheim B, Eiklid KL, Samarakoon PS

Abstract
Currarino Syndrome is a rare congenital malformation syndrome described as a triad of anorectal, sacral and presacral anomalies. Currarino Syndrome is reported to be both familial and sporadic. Familial CS is today known as an autosomal dominant disorder caused by mutations in the transcription factor MNX1. The aim of this study was to look for genetic causes of Currarino Syndrome in sporadic patients after ruling out other causes, like chromosome aberrations, disease-causing variants in possible MNX1 cooperating transcription factors and aberrant methylation in the promoter of the MNX1 gene. The hypothesis was that MNX1 was affected through interactions with other transcription factors or through other regulatory elements and thereby possibly leading to abnormal function of the gene. We performed whole exome sequencing with an additional 6Mb custom made region on chromosome 7 (GRCh37/hg19, chr7:153.138.664-159.138.663) to detect regulatory elements in non-coding regions around the MNX1 gene. We did not find any variants in genes of interest shared between the patients. However, after analyzing the whole exome sequencing data with Filtus, the in-house SNV filtration program, we did find some interesting variants in possibly relevant genes that could be explaining these patients` phenotypes. The most promising genes were ETV3L, ARID5A and NCAPD3. To our knowledge this is the first report of whole exome sequencing in sporadic CS patients.

PMID: 28456592 [PubMed - as supplied by publisher]

13 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 2017/04/30

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.

Novel missense mutation in DLL4 in a Japanese sporadic case of Adams-Oliver syndrome.

J Hum Genet. 2017 Apr 27;:

Authors: Nagasaka M, Taniguchi-Ikeda M, Inagaki H, Ouchi Y, Kurokawa D, Yamana K, Harada R, Nozu K, Sakai Y, Mishra SK, Yamaguchi Y, Morikoka I, Toda T, Kurahashi H, Iijima K

Abstract
Adams-Oliver syndrome (AOS, OMIM; 100300) is a rare genetic disease characterized by aplasia cutis congenita, terminal transverse limb defects and cutis marmorata with vascular anomalies such as congenital heart defects. The etiology of this syndrome has remained largely unknown but defective Notch signaling during vascular formation has been suggested. Here we describe a sporadic Japanese newborn case with clinically diagnosed AOS. Trio whole-exome sequencing identified a de novo, novel, heterozygous missense mutation in the Delta-like 4 ligand gene (DLL4 c.572G>A, p.Arg191His) in the patient. DLL4 functions as a requisite ligand for NOTCH1 receptor, which is essential for vascular formation. Amino acid substitution of Arg191 to His was predicted by molecular models to interfere with direct binding between DLL4 and NOTCH1. DLL4 has recently been identified as a causative gene of an autosomal dominant type of AOS with milder symptoms. The case described here showed gradual recovery from skull defects after birth and no psychomotor developmental delay has been observed. This is the second report of an AOS case with DLL4 mutation, and the phenotypic characteristics between the two cases are compared and discussed.Journal of Human Genetics advance online publication, 27 April 2017; doi:10.1038/jhg.2017.48.

PMID: 28446798 [PubMed - as supplied by publisher]

Carbamoyl phosphate synthetase 1 deficiency diagnosed by whole exome sequencing.

J Clin Lab Anal. 2017 Apr 26;:

Authors: Zhang G, Chen Y, Ju H, Bei F, Li J, Wang J, Sun J, Bu J

Abstract
BACKGROUND: Carbamoyl Phosphate Synthetase 1 deficiency (CPS1D) is a rare autosomal recessive inborn metabolic disease characterized mainly by hyperammonemia. The fatal nature of CPS1D and its similar symptoms with other urea cycle disorders (UCDs) make its diagnosis difficult, and the molecular diagnosis is hindered due to the large size of the causative gene CPS1. Therefore, the objective of the present study was to investigate the clinical applicability of exome sequencing in molecular diagnosis of CPS1D in Chinese population.
METHODS: We described two Chinese neonates presented with unconsciousness and drowsiness due to deepening encephalopathy with hyperammonemia. Whole exome sequencing was performed. Candidate mutations were validated by Sanger sequencing. In-silicon analysis was processed for the pathogenicity predictions of the identified mutations.
RESULTS: Two compound heterozygous mutations in the gene carbamoyl phosphate synthetase 1(CPS1) were identified. One is in Case 1 with two novel missense mutations (c.2537C>T, p. Pro846Leu and c.3443T>A, p.Met1148Lys), and the other one is in Case 2 with a novel missense mutation (c.1799G>A, p.Cys600Tyr) and a previously reported 12-bp deletion (c.4088_4099del, p.Leu 1363_Ile1366del). Bioinformatics deleterious predictions indicated pathogenicity of the missense mutations. Conversation analysis and homology modeling showed that the substituted amino acids were highly evolutionary conserved and necessary for enzyme stability or function.
CONCLUSION: The present study initially and successfully applied whole exome sequencing to the molecular diagnosis of CPS1D in Chinese neonates, indicating its applicability in cost-effective molecular diagnosis of CPS1D. Three novel pathogenic missense mutations were identified, expanded the mutational spectrum of the CPS1 gene.

PMID: 28444906 [PubMed - as supplied by publisher]