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1.
Hum Mutat ; 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31448840

RESUMO

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of Spastic Paraplegia type 2 [MIM# 312920], sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array Comparative Genomic Hybridization (aCGH) and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (8 herein and 9 published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT. This article is protected by copyright. All rights reserved.

2.
J Clin Endocrinol Metab ; 104(8): 3049-3067, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042289

RESUMO

CONTEXT: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait. OBJECTIVE: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI. DESIGN, SETTING, AND PARTICIPANTS: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity. RESULTS: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds. CONCLUSIONS: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.

3.
Genome Med ; 11(1): 25, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31014393

RESUMO

BACKGROUND: Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. Recently, post-zygotic de novo triplications adjacent to copy-number neutral genomic intervals with runs of homozygosity (ROH) have been shown to result in uniparental isodisomy (UPD). The genomic structure of these complex genomic rearrangements (CGRs) shows a consistent pattern of an inverted triplication flanked by duplications (DUP-TRP/INV-DUP) formed by an iterative DNA replisome template-switching mechanism during replicative repair of a single-ended, double-stranded DNA (seDNA), the ROH results from an interhomolog or nonsister chromatid template switch. It has been postulated that these CGRs may lead to genetic abnormalities in carriers due to dosage-sensitive genes mapping within the copy-number variant regions, homozygosity for alleles at a locus causing an autosomal recessive (AR) disease trait within the ROH region, or imprinting-associated diseases. METHODS: Here, we report a family wherein the affected subject carries a de novo 2.2-Mb TRP followed by 42.2 Mb of ROH and manifests clinical features overlapping with those observed in association with chromosome 14 maternal UPD (UPD(14)mat). UPD(14)mat can cause clinical phenotypic features enabling a diagnosis of Temple syndrome. This CGR was then molecularly characterized by high-density custom aCGH, genome-wide single-nucleotide polymorphism (SNP) and methylation arrays, exome sequencing (ES), and the Oxford Nanopore long-read sequencing technology. RESULTS: We confirmed the postulated DUP-TRP/INV-DUP structure by multiple orthogonal genomic technologies in the proband. The methylation status of known differentially methylated regions (DMRs) on chromosome 14 revealed that the subject shows the typical methylation pattern of UPD(14)mat. Consistent with these molecular findings, the clinical features overlap with those observed in Temple syndrome, including speech delay. CONCLUSIONS: These data provide experimental evidence that, in humans, triplication can lead to segmental UPD and imprinting disease. Importantly, genotype/phenotype analyses further reveal how a post-zygotically generated complex structural variant, resulting from a replication-based mutational mechanism, contributes to expanding the clinical phenotype of known genetic syndromes. Mechanistically, such events can distort transmission genetics resulting in homozygosity at a locus for which only one parent is a carrier as well as cause imprinting diseases.

4.
J Endocr Soc ; 2(10): 1100-1108, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30525125

RESUMO

We describe a 4-year-old boy with developmental delay who was found to carry by clinical grade (CG) molecular cytogenetics (MCs) a chromosome Xq26 microduplication. The report prompted a referral of the patient for possible X-linked acrogigantism (X-LAG), a well-defined condition (MIM300942) due to chromosomal microduplication of a nearby region. The patient was evaluated clinically and investigated for endocrine abnormalities related to X-LAG and not only did he not have acrogigantism, but his growth parameters and other hormones were all normal. We then performed high definition MCs and the duplication copy number variant (CNV) was confirmed to precisely map outside the X-LAG critical region and definitely did not harbor the X-LAG candidate gene, GPR101. The patient's phenotype resembled that of other patients with Xq26 CNVs. The case is instructive for the need for high definition MCs when CG MCs' results are inconsistent with the patient's phenotype. It is also useful for further supporting the contention that GPR101 is the gene responsible for X-LAG.

5.
Genome Biol ; 16: 240, 2015 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-26537248

RESUMO

BACKGROUND: Embryonic lethality is a recognized phenotypic expression of individual gene mutations in model organisms. However, identifying embryonic lethal genes in humans is challenging, especially when the phenotype is manifested at the preimplantation stage. RESULTS: In an ongoing effort to exploit the highly consanguineous nature of the Saudi population to catalog recessively acting embryonic lethal genes in humans, we have identified two families with a female-limited infertility phenotype. Using autozygosity mapping and whole exome sequencing, we map this phenotype to a single mutation in TLE6, a maternal effect gene that encodes a member of the subcortical maternal complex in mammalian oocytes. Consistent with the published phenotype of mouse Tle6 mutants, embryos from female patients who are homozygous for the TLE6 mutation fail to undergo early cleavage, with resulting sterility. The human mutation abrogates TLE6 phosphorylation, a step that is reported to be critical for the PKA-mediated progression of oocyte meiosis II. Furthermore, the TLE6 mutation impairs its binding to components of the subcortical maternal complex. CONCLUSION: In this first report of a human defect in a member of the subcortical maternal subcritical maternal complex, we show that the TLE6 mutation is gender-specific and leads to the earliest known human embryonic lethality phenotype.


Assuntos
Desenvolvimento Embrionário/genética , Infertilidade Feminina/genética , Oócitos/crescimento & desenvolvimento , Fatores de Transcrição/genética , Adulto , Animais , Consanguinidade , Feminino , Fertilização In Vitro , Regulação da Expressão Gênica no Desenvolvimento , Genes Letais , Ligação Genética , Humanos , Infertilidade Feminina/patologia , Masculino , Meiose/genética , Camundongos , Mutação , Oócitos/patologia , Fenótipo , Arábia Saudita
6.
Hum Genet ; 134(8): 815-22, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25957586

RESUMO

Cutis Marmorata Telangiectatica Congenita (CMTC) is a congenital localized or generalized vascular anomaly, usually sporadic in occurrence. It can be associated with other cutaneous or systemic manifestations. About 300 cases have been reported. The molecular etiology remains largely unknown. The main purpose of this study is to delineate the molecular basis for a syndromic CMTC phenotype in a consanguineous Saudi family. Clinical phenotyping including detailed neurological imaging, followed by autozygosity mapping and trio whole exome sequencing (WES) are also studied. We have identified a homozygous truncating mutation in ARL6IP6 as the likely cause of a syndromic form of CMTC associated with major dysmorphism, developmental delay, transient ischemic attacks and cerebral vascular malformations. This gene was previously implicated by genome wide association study (GWAS) as a susceptibility locus to ischemic stroke in young adults. We identify ARL6IP6 as a novel candidate gene for a syndromic form of CMTC. This suggests that ischemic stroke or transient ischemic attacks (TIA) may represent, at least in some cases, the mild end of a phenotypic spectrum that has at its severe end autosomal recessive CMTC. This finding contributes to a growing appreciation of the continuum of Mendelian and common complex diseases.


Assuntos
Isquemia Encefálica/genética , Malformações Vasculares do Sistema Nervoso Central/genética , Loci Gênicos , Predisposição Genética para Doença , Proteínas de Choque Térmico/genética , Mutação , Dermatopatias Vasculares/genética , Acidente Vascular Cerebral/genética , Telangiectasia/congênito , Adulto , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Síndrome , Telangiectasia/genética
7.
J Med Genet ; 52(6): 400-4, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25748484

RESUMO

BACKGROUND: Klippel-Feil anomaly (KFA) can be seen in a number of syndromes. We describe an apparently novel syndromic association with KFA. METHODS: Clinical phenotyping of two consanguineous families followed by combined autozygome/exome analysis. RESULTS: Two patients from two apparently unrelated families shared a strikingly similar phenotype characterised by KFA, myopathy, mild short stature, microcephaly, and distinctive facies. They shared a single founder autozygous interval in which whole exome sequencing revealed a truncating mutation in MYO18B. There was virtually complete loss of the transcript in peripheral blood, indicative of nonsense-mediated decay. Electron microscopy of muscle confirms abnormal myosin filaments with accompanying myopathic changes. CONCLUSIONS: Deficiency of MYO18B is linked to a novel developmental disorder which combines KFA with myopathy. This suggests a widespread developmental role for this gene in humans, as observed for its murine ortholog.


Assuntos
Facies , Síndrome de Klippel-Feil/diagnóstico , Síndrome de Klippel-Feil/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Mutação , Miosinas/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Criança , Mapeamento Cromossômico , Consanguinidade , Análise Mutacional de DNA , Feminino , Homozigoto , Humanos , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Linhagem , Fenótipo , Coluna Vertebral/patologia , Síndrome
8.
Cell Rep ; 10(2): 148-61, 2015 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-25558065

RESUMO

Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.


Assuntos
Doenças do Sistema Nervoso Central/genética , Estudos de Associação Genética , Doenças do Sistema Nervoso Central/patologia , Mapeamento Cromossômico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
9.
J Med Genet ; 51(4): 224-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24399846

RESUMO

BACKGROUND: Epileptic encephalopathy is a broad clinical category that is highly heterogeneous genetically. OBJECTIVE: To describe a multiplex extended consanguineous family that defines a molecularly novel subtype of early infantile epileptic encephalopathy. METHODS: Autozygosity mapping and exome sequencing for the identification of the causal mutation. This was followed by expression analysis of the candidate gene. RESULTS: In an extended multigenerational family with six affected individuals, a single novel disease locus was identified on chromosome 12p13.31-p13.2. Within that locus, the only deleterious novel exomic variant was a homozygous truncating mutation in NECAP1, encoding a clathrin-accessory protein. The mutation was confirmed to trigger nonsense-mediated decay. Consistent with previous reports, we show that NECAP1 is highly enriched in the central nervous system. CONCLUSIONS: NECAP1 is known to regulate clathrin-mediated endocytosis in synapses. The mutation we report here links for the first time this trafficking pathway in early infantile epileptic encephalopathy.


Assuntos
Subunidades alfa do Complexo de Proteínas Adaptadoras/genética , Proteínas de Membrana/genética , Mutação/genética , Espasmos Infantis/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Análise Mutacional de DNA , Família , Evolução Fatal , Feminino , Loci Gênicos/genética , Homozigoto , Humanos , Lactente , Masculino , Camundongos , Linhagem
11.
Am J Hum Genet ; 93(2): 313-20, 2013 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-23830514

RESUMO

Myopia is an extremely common eye disorder but the pathogenesis of its isolated form, which accounts for the overwhelming majority of cases, remains poorly understood. There is strong evidence for genetic predisposition to myopia, but determining myopia genetic risk factors has been difficult to achieve. We have identified Mendelian forms of myopia in four consanguineous families and implemented exome/autozygome analysis to identify homozygous truncating variants in LRPAP1 and CTSH as the likely causal mutations. LRPAP1 encodes a chaperone of LRP1, which is known to influence TGF-ß activity. Interestingly, we observed marked deficiency of LRP1 and upregulation of TGF-ß in cells from affected individuals, the latter being consistent with available data on the role of TGF-ß in the remodeling of the sclera in myopia and the high frequency of myopia in individuals with Marfan syndrome who characteristically have upregulation of TGF-ß signaling. CTSH, on the other hand, encodes a protease and we show that deficiency of the murine ortholog results in markedly abnormal globes consistent with the observed human phenotype. Our data highlight a role for LRPAP1 and CTSH in myopia genetics and demonstrate the power of Mendelian forms in illuminating new molecular mechanisms that may be relevant to common phenotypes.


Assuntos
Catepsina H/genética , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Síndrome de Marfan/genética , Mutação , Miopia/genética , Fator de Crescimento Transformador beta/genética , Adolescente , Animais , Catepsina H/metabolismo , Criança , Pré-Escolar , Feminino , Expressão Gênica , Predisposição Genética para Doença , Homozigoto , Humanos , Lactente , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Síndrome de Marfan/metabolismo , Síndrome de Marfan/patologia , Camundongos , Miopia/metabolismo , Miopia/patologia , Linhagem , Fenótipo , Esclera/metabolismo , Esclera/patologia , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta/metabolismo
12.
J Med Genet ; 50(7): 425-30, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23620220

RESUMO

BACKGROUND: Intellectual disability (ID) is one of the most common forms of disability worldwide, displaying a wide range of aetiologies and affecting nearly 2% of the global population. OBJECTIVE: To describe a novel autosomal recessive form of ID with strabismus and its underlying aetiology. MATERIALS AND METHODS: Autozygosity mapping, linkage analysis and exome sequencing were performed in a large multiplex consanguineous family that segregates ID and strabismus. Exome sequencing was independently performed in three other consanguineous families segregating the same disease. Direct sequencing of the resulting candidate gene was performed in four additional families with the same phenotype. RESULTS: A single missense mutation was identified in ADAT3 in all studied families on an ancient ancestral haplotype. This gene encodes one of two eukaryotic proteins that are necessary for the deamination of adenosine at position 34 to inosine in t-RNA. Our results show the first human mutation in the t-RNA editing machinery and expand the landscape of pathways involved in the pathogenesis of ID.


Assuntos
Adenosina Desaminase/genética , Deficiência Intelectual/genética , RNA de Transferência/genética , Estrabismo/genética , Sequência de Aminoácidos , Sequência de Bases , Estudos de Coortes , Consanguinidade , Exoma/genética , Feminino , Genes Recessivos , Ligação Genética , Haplótipos , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , RNA de Transferência/metabolismo
13.
J AAPOS ; 16(6): 571-2, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23158549

RESUMO

Nonsyndromic primary newborn glaucoma, the most severe form of primary congenital glaucoma, typically is bilateral and often the result of CYP1B1 mutations, particularly in certain consanguineous populations. Truly unilateral cases are uncommon and genetically not well studied. During a 9-year period, we tested 5 consecutive children with unilateral primary newborn glaucoma from Saudi Arabia, where CYP1B1 mutations are the cause for 91% of bilateral primary newborn glaucoma cases. None of these children with unilateral primary newborn glaucoma harbored CYP1B1 mutations, suggesting that in this population the pathogenesis of unilateral disease differs from that of bilateral disease.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Hidroftalmia/genética , Criança , Pré-Escolar , Consanguinidade , Citocromo P-450 CYP1B1 , Análise Mutacional de DNA , Feminino , Humanos , Hidroftalmia/diagnóstico , Hidroftalmia/etnologia , Pressão Intraocular , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Arábia Saudita/epidemiologia , Tonometria Ocular
14.
Genet Med ; 14(12): 955-62, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22935719

RESUMO

BACKGROUND: Pediatric cataract is an important preventable blinding disease. Previous studies have estimated 10-25% of cases to be genetic in etiology. METHODS: In an effort to characterize the genetics of cataract in our population, we have conducted a comprehensive clinical and genomic analysis (including autozygome and exome analysis) on a series of 38 index patients. RESULTS: Pediatric cataract is genetic in at least 79% of the study families. Although crystallins accounted for most of the mutant alleles, mutations in other genes were encountered, including recessive mutations in genes that usually cause the disease in a dominant manner. In addition, several novel candidate genes (MFSD6L, AKR1E2, RNLS, and CYP51A1) were identified. CONCLUSION: Pediatric cataract is typically a genetic disease, usually autosomal recessive, in Saudi Arabia. Although defining a specific cataract phenotype can sometimes predict the genetic cause, genomic analysis is often required to unravel the causative mutation given the marked genetic heterogeneity. The identified novel candidate genes require independent confirmation in future studies.


Assuntos
Catarata/genética , Criança , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Exoma , Proteínas do Olho/genética , Feminino , Efeito Fundador , Estudos de Associação Genética , Genoma Humano , Homozigoto , Humanos , Proteínas de Filamentos Intermediários/genética , Masculino , Monoaminoxidase/genética , Mutação de Sentido Incorreto , N-Acetilglucosaminiltransferases/genética , Receptor EphA2/genética , Arábia Saudita , Esterol 14-Desmetilase/genética , Fatores de Transcrição/genética , Cadeia B de beta-Cristalina/genética
15.
Hum Mutat ; 33(10): 1423-8, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22693042

RESUMO

Joubert syndrome (JS) is a ciliopathy that is defined primarily by typical cerebellar structural and ocular motility defects. The genetic heterogeneity of this condition is significant with 16 genes identified to date. We have used a combination of autozygome-guided candidate gene mutation analysis and exome sequencing to identify the causative mutation in a series of 12 families. The autozygome approach identified mutations in RPGRIP1L, AHI1, TMEM237, and CEP290, while exome sequencing revealed families with truncating mutations in TCTN1 and C5ORF42. Our study, the largest comprehensive molecular series on JS, provides independent confirmation of the recently reported TCTN1, TMEM237, and C5ORF42 as bona fide JS disease genes, and expands the allelic heterogeneity of this disease.


Assuntos
Doenças Cerebelares/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Anormalidades Múltiplas , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Doenças Cerebelares/etnologia , Cerebelo/anormalidades , Criança , Pré-Escolar , Exoma/genética , Anormalidades do Olho/etnologia , Feminino , Estudos de Associação Genética , Humanos , Lactente , Doenças Renais Císticas/etnologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Linhagem , Retina/anormalidades , Arábia Saudita
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