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1.
Hum Genet ; 139(12): 1565-1574, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32562050

RESUMO

COCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly hearing loss in mice and humans. Two forms of hearing loss are linked to mutations in COCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic hearing loss (DFNB110) via nonsense variants. Using a combination of targeted gene panels, exome sequencing, and functional studies, we identified four novel pathogenic variants (two nonsense variants, one missense, and one inframe deletion) in COCH as the cause of autosomal recessive hearing loss in a multi-ethnic cohort. To investigate whether the non-truncating variants exert their effect via a loss-of-function mechanism, we used minigene splicing assays. Our data showed both the missense and inframe deletion variants altered RNA splicing by creating an exon splicing silencer and abolishing an exon splicing enhancer, respectively. Both variants create frameshifts and are predicted to result in a null allele. This study confirms the involvement of loss-of-function mutations in COCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA splicing, and highlights the need to investigate the effect of coding variants on RNA splicing.


Assuntos
Surdez/genética , Proteínas da Matriz Extracelular/genética , Genes Recessivos/genética , Mutação com Perda de Função/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cóclea/metabolismo , Cóclea/patologia , Códon sem Sentido/genética , Surdez/patologia , Éxons/genética , Feminino , Mutação da Fase de Leitura/genética , Humanos , Masculino , Linhagem
2.
Hum Genet ; 139(11): 1429-1441, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32488467

RESUMO

Autozygosity-driven exome analysis has been shown effective for identification of genes underlying recessive diseases especially in countries of the so-called Greater Middle East (GME), where high consanguinity unravels the phenotypic effects of recessive alleles and large family sizes facilitate homozygosity mapping. In Italy, as in most European countries, consanguinity is estimated low. Nonetheless, consanguineous Italian families are not uncommon in publications of genetic findings and are often key to new associations of genes with rare diseases. We collected 52 patients from 47 consanguineous families with suspected recessive diseases, 29 originated in GME countries and 18 of Italian descent. We performed autozygosity-driven exome analysis by detecting long runs of homozygosity (ROHs > 1.5 Mb) and by prioritizing candidate clinical variants within. We identified a pathogenic synonymous variant that had been previously missed in NARS2 and we increased an initial high diagnostic rate (47%) to 55% by matchmaking our candidate genes and including in the analysis shorter ROHs that may also happen to be autozygous. GME and Italian families contributed to diagnostic yield comparably. We found no significant difference either in the extension of the autozygous genome, or in the distribution of candidate clinical variants between GME and Italian families, while we showed that the average autozygous genome was larger and the mean number of candidate clinical variants was significantly higher (p = 0.003) in mutation-positive than in mutation-negative individuals, suggesting that these features influence the likelihood that the disease is autozygosity-related. We highlight the utility of autozygosity-driven genomic analysis also in countries and/or communities, where consanguinity is not widespread cultural tradition.


Assuntos
Testes Genéticos/métodos , Genoma Humano/genética , Mapeamento Cromossômico/métodos , Consanguinidade , Exoma/genética , Família , Feminino , Genes Recessivos/genética , Humanos , Itália , Masculino , Oriente Médio , Mutação/genética , Linhagem
3.
BMC Med Genet ; 21(1): 79, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295532

RESUMO

BACKGROUND: Congenital chloride diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness. CASE PRESENTATION: We report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD. CONCLUSIONS: Familial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples.


Assuntos
Antiportadores de Cloreto-Bicarbonato/genética , Diarreia/congênito , Bócio Nodular/genética , Perda Auditiva Neurossensorial/genética , Erros Inatos do Metabolismo/genética , Transportadores de Sulfato/genética , Diarreia/diagnóstico , Diarreia/genética , Diarreia/patologia , Feminino , Genes Recessivos/genética , Testes Genéticos , Bócio Nodular/diagnóstico , Bócio Nodular/patologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Humanos , Lactente , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/patologia , Mutação , Linhagem , Gravidez , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/patologia , Irmãos
4.
PLoS One ; 15(3): e0229564, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119688

RESUMO

The introduction of high-yielding semi-dwarf varieties of wheat into cultivation has led to a "green revolution." This has required intensive research into various sources of dwarfism in wheat. However, there has been very little advancement in research on dwarfing genes in rye in comparison to wheat or barley. So far, three dominant dwarfing genes (Ddw1, Ddw3, and Ddw4) and three recessive genes (ct1, ct2, and np) have been characterized and precisely mapped in rye. There is no complete catalog of dwarfing genes available in rye. This paper presents an identification of the source of dwarfism and preliminary characterization of the new recessive gene dw9 from the BK-1 line. The gene was mapped on the long arm of the 6R chromosome and belongs to the GA-insensitive group. The initial characterization of the influence of this gene on morphological traits shows that it significantly affects the decrease of yielding trait parameters. A full evaluation can be performed after detailed breeding studies.


Assuntos
Nanismo/genética , Secale/genética , Biometria/métodos , Mapeamento Cromossômico/métodos , Cromossomos de Plantas/genética , Resistência à Doença/genética , Genes de Plantas/genética , Genes Recessivos/genética , Fenótipo , Melhoramento Vegetal/métodos , Doenças das Plantas/genética
5.
BMC Med Genet ; 21(1): 59, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32209057

RESUMO

BACKGROUND: Intellectual disability (ID) is both a clinically diverse and genetically heterogeneous group of disorder, with an onset of cognitive impairment before the age of 18 years. ID is characterized by significant limitations in intellectual functioning and adaptive behaviour. The identification of genetic variants causing ID and neurodevelopmental disorders using whole-exome sequencing (WES) has proven to be successful. So far more than 1222 primary and 1127 candidate genes are associated with ID. METHODS: To determine pathogenic variants causative of ID in three unrelated consanguineous Pakistani families, we used a combination of WES, homozygosity-by-descent mapping, de-deoxy sequencing and bioinformatics analysis. RESULTS: Rare pathogenic single nucleotide variants identified by WES which passed our filtering strategy were confirmed by traditional Sanger sequencing and segregation analysis. Novel and deleterious variants in VPS53, GLB1, and MLC1, genes previously associated with variable neurodevelopmental anomalies, were found to segregate with the disease in the three families. CONCLUSIONS: This study expands our knowledge on the molecular basis of ID as well as the clinical heterogeneity associated to different rare genetic causes of neurodevelopmental disorders. This genetic study could also provide additional knowledge to help genetic assessment as well as clinical and social management of ID in Pakistani families.


Assuntos
Consanguinidade , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Polimorfismo Genético , Proteínas de Transporte Vesicular/genética , beta-Galactosidase/genética , Criança , Pré-Escolar , Família , Feminino , Genes Recessivos/genética , Heterogeneidade Genética , Testes Genéticos , Homozigoto , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Masculino , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Paquistão/epidemiologia , Linhagem , Sequenciamento Completo do Exoma
6.
Plant Sci ; 293: 110411, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32081260

RESUMO

In Brassica napus, pod number and pod density are critical factors to determine seed yield. Although the pod density is an essential yield trait, the regulation of yield formation in oil crops, as well as the genetic and molecular mechanisms, are poorly understood. In this study, we characterized a rapeseed high-density pod mutant (dpt247) from composite hybridization. To shed some light on the nature of this mutation, it was investigated morphologically, anatomically, physiologically, genetically and transcriptomically. The mutant plant showed noticeable phenotypic differences in comparison with the control plant, including reduced plant height and primary branch length, decreased number of primary branches, significantly increased number of pod on the main inflorescence, and more compact pod distribution. Besides, the mutant had higher levels of indole-3-acetic acid (IAA) and zeatin riboside (ZR) in the shoot apical meristem (SAM). The dense pod trait was controlled by two major recessive genes identified in the segregating genetic populations of GRE501 and dpt247. RNA sequencing indicated genes participated in auxin, cytokinin and WUS/CLV signalling pathway in dpt247 were more active in the mutant. These results provide important information for understanding the regulation of yield formation and high yield breeding in rapeseed.


Assuntos
Brassica napus/genética , Genes Recessivos/genética , Sementes/genética , Divisão Celular , Cromossomos de Plantas , Regulação da Expressão Gênica de Plantas , Genes de Plantas/genética , Ácidos Indolacéticos/metabolismo , Isopenteniladenosina/análogos & derivados , Fenótipo , Brotos de Planta , Sementes/fisiologia , Análise de Sequência de RNA , Transcriptoma
7.
Sci Rep ; 10(1): 1413, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996704

RESUMO

A substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking. Therefore, genetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Disease-causing variants, including newly discovered variants, were identified in 57.5% of the probands of the KND cohort. Among the patients with the previous reported pathogenic variants, 35.1% inherited these variants in a recessive manner. Genes that cause recessive disorders in our cohort tend to be less constrained by loss-of-function variants and were enriched in lipid metabolism and mitochondrial functions. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.


Assuntos
Genes Recessivos/genética , Triagem de Portadores Genéticos/métodos , Transtornos do Neurodesenvolvimento/genética , Adolescente , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Triagem de Portadores Genéticos/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , República da Coreia/epidemiologia , Sequenciamento Completo do Exoma , Adulto Jovem
8.
BMC Neurol ; 20(1): 2, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900114

RESUMO

BACKGROUND: Spastic paraplegia type 11 (SPG11) mutations are the most frequent cause of autosomal recessive hereditary spastic paraplegia (ARHSP). We are aiming to identify the causative mutations in SPG11 among families referred to our center with ARHSP in a Chinese population. METHODS: Targeted next-generation sequencing was performed on the patients to identify disease-causing mutations. Variants were analyzed according to their predicted pathogenicity and their relevance to the clinical phenotypes. The segregation in the family members was validated by Sanger sequencing. RESULTS: A total of 12 mutations in SPG11 gene from 9 index cases were identified, including 6 frameshift mutations, 3 missense mutations, 1 nonsense mutation, 1 splicing mutation, and 1 intron deletion mutation. In 6 of these patients, the mutations were homozygous, and the other 3 patients carried two compound heterozygous mutations. Six mutations were novel; 2 were classified as pathogenic, 1 were considered as likely pathogenic, and the other 3 were variants of unknown significance. Additionally, 1 missense heterozygous variant we found was also carried by amyotrophic lateral sclerosis (ALS) patient. Clinically and electrophysiologically, some of our ARHSP patients partially shared various features of autosomal-recessive juvenile amyotrophic lateral sclerosis (ARJALS), including combination of both UMN and LMN degeneration. CONCLUSIONS: The results contribute to extending of the SPG11 gene mutation spectrum and emphasizing a putative link between ARHSP and ARJALS.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Genes Recessivos/genética , Proteínas/genética , Paraplegia Espástica Hereditária , Adolescente , Adulto , Criança , China , Feminino , Humanos , Masculino , Mutação/genética , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/fisiopatologia , Adulto Jovem
9.
Microbiol Immunol ; 64(1): 76-82, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31687790

RESUMO

The pea cyv1 gene is a yet-to-be-identified recessive resistance gene that inhibits the infection of clover yellow vein virus (ClYVV). Previous studies confirmed that the cell-to-cell movement of ClYVV is inhibited in cyv1-carrying pea plants; however, the effect of cyv1 on viral replication remains unknown. In this study, we developed a new pea protoplast transfection method to investigate ClYVV propagation at the single-cell level. Using this method, we revealed that ClYVV accumulates to similar levels in both ClYVV-susceptible and cyv1-carrying pea protoplasts. Thus, the cyv1-mediated resistance would not suppress intracellular ClYVV replication.


Assuntos
Proliferação de Células , Citoplasma/virologia , Resistência à Doença/genética , Genes de Plantas/genética , Ervilhas/genética , Resistência à Doença/imunologia , Genes Recessivos/genética , Proteínas de Fluorescência Verde/genética , Ervilhas/imunologia , Ervilhas/virologia , Doenças das Plantas/imunologia , Doenças das Plantas/virologia , Potyvirus , RNA Viral , Replicação Viral
10.
Mol Genet Genomics ; 295(1): 233-249, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31673754

RESUMO

In Chinese cabbage, hybrid seed production is performed using male sterility lines, an important approach to heterosis utilization. In this study, a stably inherited male sterile mutant msm was obtained from the 'FT'-doubled haploid line of Chinese cabbage using isolated microspore culture combined with 60Co γ-ray mutagenesis. The genetic backgrounds of 'FT' and msm were highly consistent; however, compared with wild-type 'FT', msm exhibited completely degenerated stamens and no pollen phenotype. Other characters showed no significant differences. Cytological observations revealed that stamen abortion in msm begins during the tetrad period and that tapetum cells were abnormally expanded and highly vacuolated, leading to microspore abortion. Genetic analysis indicated that the msm mutant phenotype is controlled by a single recessive nuclear gene. Comparative transcriptome analysis of 'FT' and msm flower buds using RNA-Seq technology revealed 1653 differentially expressed genes, among which, a large number associated with male sterility were detected, including 64 pollen development- and pollen tube growth-related genes, 94 pollen wall development-related genes, 11 phytohormone-related genes, and 16 transcription factor-related genes. An overwhelming majority of these genes were down-regulated in msm compared with 'FT'. Furthermore, KEGG pathway analysis indicated that a variety of carbohydrate metabolic and lipid metabolic pathways were significantly enriched, which may be related to pollen abortion. The expression patterns of 24 male sterility-related genes were analyzed using qRT-PCR. In addition, 24,476 single-nucleotide polymorphisms and 413,073 insertion-deletion events were specifically detected in msm. These results will facilitate elucidation of the regulatory mechanisms underlying male sterility in Chinese cabbage.


Assuntos
Brassica/genética , Genes de Plantas/genética , Infertilidade das Plantas/genética , Flores/genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica de Plantas/genética , Genes Recessivos/genética , Reguladores de Crescimento de Planta/genética , Proteínas de Plantas/genética , Pólen/genética , RNA-Seq/métodos , Transcriptoma/genética , Sequenciamento Completo do Exoma/métodos
11.
Brain ; 143(2): 491-502, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31851307

RESUMO

Primary familial brain calcification is a monogenic disease characterized by bilateral calcifications in the basal ganglia and other brain regions, and commonly presents motor, psychiatric, and cognitive symptoms. Currently, four autosomal dominant (SLC20A2, PDGFRB, PDGFB, XPR1) and one autosomal recessive (MYORG) causative genes have been identified. Compared with patients with autosomal dominant primary familial brain calcification, patients with the recessive form of the disease present with more severe clinical and imaging phenotypes, and deserve more clinical and research attention. Biallelic mutations in MYORG cannot explain all autosomal recessive primary familial brain calcification cases, indicating the existence of novel autosomal recessive genes. Using homozygosity mapping and whole genome sequencing, we detected a homozygous frameshift mutation (c.140delT, p.L48*) in the JAM2 gene in a consanguineous family with two affected siblings diagnosed with primary familial brain calcification. Further genetic screening in a cohort of 398 probands detected a homozygous start codon mutation (c.1A>G, p.M1?) and compound heterozygous mutations [c.504G>C, p.W168C and c.(67+1_68-1)_(394+1_395-1), p.Y23_V131delinsL], respectively, in two unrelated families. The clinical phenotypes of the four patients included parkinsonism (3/4), dysarthria (3/4), seizures (1/4), and probable asymptomatic (1/4), with diverse onset ages. All patients presented with severe calcifications in the cortex in addition to extensive calcifications in multiple brain areas (lenticular nuclei, caudate nuclei, thalamus, cerebellar hemispheres, ± brainstem; total calcification scores: 43-77). JAM2 encodes junctional adhesion molecule 2, which is highly expressed in neurovascular unit-related cell types (endothelial cells and astrocytes) and is predominantly localized on the plasma membrane. It may be important in cell-cell adhesion and maintaining homeostasis in the CNS. In Chinese hamster ovary cells, truncated His-tagged JAM2 proteins were detected by western blot following transfection of p.Y23_V131delinsL mutant plasmid, while no protein was detected following transfection of p.L48* or p.1M? mutant plasmids. In immunofluorescence experiments, the p.W168C mutant JAM2 protein failed to translocate to the plasma membrane. We speculated that mutant JAM2 protein resulted in impaired cell-cell adhesion functions and reduced integrity of the neurovascular unit. This is similar to the mechanisms of other causative genes for primary familial brain calcification or brain calcification syndromes (e.g. PDGFRB, PDGFB, MYORG, JAM3, and OCLN), all of which are highly expressed and functionally important in the neurovascular unit. Our study identifies a novel causative gene for primary familial brain calcification, whose vital function and high expression in the neurovascular unit further supports impairment of the neurovascular unit as the root of primary familial brain calcification pathogenesis.


Assuntos
Encefalopatias/genética , Encéfalo/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Células Endoteliais/metabolismo , Adulto , Encéfalo/patologia , Encefalopatias/metabolismo , Calcinose/genética , Feminino , Genes Recessivos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Linhagem , Fenótipo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo
12.
Am J Hum Genet ; 105(5): 1023-1029, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31630788

RESUMO

We describe unrelated individuals with ichthyosis, failure to thrive, thrombocytopenia, photophobia, and progressive hearing loss. Each have bi-allelic mutations in AP1B1, the gene encoding the ß subunit of heterotetrameric adaptor protein 1 (AP-1) complexes, which mediate endomembrane polarization, sorting, and transport. In affected keratinocytes the AP-1 ß subunit is lost, and the γ subunit is greatly reduced, demonstrating destabilization of the AP-1 complex. Affected cells and tissue contain an abundance of abnormal vesicles and show hyperproliferation, abnormal epidermal differentiation, and derangement of intercellular junction proteins. Transduction of affected cells with wild-type AP1B1 rescues the vesicular phenotype, conclusively establishing that loss of AP1B1 function causes this disorder.


Assuntos
Complexo 1 de Proteínas Adaptadoras/genética , Subunidades beta do Complexo de Proteínas Adaptadoras/genética , Surdez/genética , Genes Recessivos/genética , Ictiose/genética , Mutação/genética , Fotofobia/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Feminino , Perda Auditiva/genética , Humanos , Masculino , Fenótipo , Subunidades Proteicas/genética , Transporte Proteico/genética , Trombocitopenia/genética
13.
Nat Genet ; 51(7): 1092-1098, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209396

RESUMO

Autism spectrum disorder (ASD) affects up to 1 in 59 individuals1. Genome-wide association and large-scale sequencing studies strongly implicate both common variants2-4 and rare de novo variants5-10 in ASD. Recessive mutations have also been implicated11-14 but their contribution remains less well defined. Here we demonstrate an excess of biallelic loss-of-function and damaging missense mutations in a large ASD cohort, corresponding to approximately 5% of total cases, including 10% of females, consistent with a female protective effect. We document biallelic disruption of known or emerging recessive neurodevelopmental genes (CA2, DDHD1, NSUN2, PAH, RARB, ROGDI, SLC1A1, USH2A) as well as other genes not previously implicated in ASD including FEV (FEV transcription factor, ETS family member), which encodes a key regulator of the serotonergic circuitry. Our data refine estimates of the contribution of recessive mutation to ASD and suggest new paths for illuminating previously unknown biological pathways responsible for this condition.


Assuntos
Desequilíbrio Alélico , Transtorno do Espectro Autista/genética , Genes Recessivos/genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Genoma Humano , Humanos , Masculino , Sequenciamento Completo do Exoma
14.
Genet Res (Camb) ; 101: e8, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31190668

RESUMO

Compound heterozygotes occur when different variants at the same locus on both maternal and paternal chromosomes produce a recessive trait. Here we present the tool VarCount for the quantification of variants at the individual level. We used VarCount to characterize compound heterozygous coding variants in patients with epileptic encephalopathy and in the 1000 Genomes Project participants. The Epi4k data contains variants identified by whole exome sequencing in patients with either Lennox-Gastaut Syndrome (LGS) or infantile spasms (IS), as well as their parents. We queried the Epi4k dataset (264 trios) and the phased 1000 Genomes Project data (2504 participants) for recessive variants. To assess enrichment, transcript counts were compared between the Epi4k and 1000 Genomes Project participants using minor allele frequency (MAF) cutoffs of 0.5 and 1.0%, and including all ancestries or only probands of European ancestry. In the Epi4k participants, we found enrichment for rare, compound heterozygous variants in six genes, including three involved in neuronal growth and development - PRTG (p = 0.00086, 1% MAF, combined ancestries), TNC (p = 0.022, 1% MAF, combined ancestries) and MACF1 (p = 0.0245, 0.5% MAF, EU ancestry). Due to the total number of transcripts considered in these analyses, the enrichment detected was not significant after correction for multiple testing and higher powered or prospective studies are necessary to validate the candidacy of these genes. However, PRTG, TNC and MACF1 are potential novel recessive epilepsy genes and our results highlight that compound heterozygous variants should be considered in sporadic epilepsy.


Assuntos
Epilepsia/genética , Epilepsia/metabolismo , Análise de Sequência de DNA/métodos , Adulto , Alelos , Exoma , Feminino , Frequência do Gene/genética , Genes Recessivos/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Heterozigoto , Humanos , Lactente , Recém-Nascido , Síndrome de Lennox Gastaut/genética , Síndrome de Lennox Gastaut/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas dos Microfilamentos/genética , Mutação , Fenótipo , Estudos Prospectivos , Espasmos Infantis/genética , Espasmos Infantis/metabolismo , Tenascina/genética
15.
JAMA Netw Open ; 2(6): e195752, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31199449

RESUMO

Importance: The PROM1 gene, commonly associated with cone-rod dystrophies, may have dominant or recessive phenotypes that influence disease onset and severity. Objective: To characterize the clinical phenotype and molecular genetic variations in patients with PROM1 variants. Design, Setting, and Participants: This case-series study was conducted at 2 specialist retinal genetics clinics and examined 19 consecutively enrolled patients with PROM1-related retinal degeneration. Data were collected and analyzed from May 2018 to December 2018. Main Outcomes and Measures: Results of ophthalmic examination, retinal imaging, and molecular genetic analysis by next-generation sequencing. Results: Of 19 patients, 13 (68%) were women, and age ranged from 11 to 70 years. All patients presented with central visual loss, with or without photophobia. Individuals with recessive variants commonly had severe loss of visual acuity by their 20s, whereas the dominant variant was associated with a milder phenotype, with most patients retaining good vision into late adulthood. The recessive cases were associated with a panretinal dystrophy of cone-rod phenotype with early macular involvement, whereas the dominant variants were associated with a cone-rod phenotype that was restricted to the macula with predominantly cone dysfunction. Next-generation sequencing identified 3 novel and 9 previously reported variants in PROM1. Recessive mutations included 6 truncating variants (3 nonsense and 3 frameshift), 4 splice site variants, and 1 missense variant. All 6 dominant variants were associated with a c.1117C>T missense variant. The variants were distributed throughout the PROM1 genomic sequence with no specific clustering on protein domains. Conclusions and Relevance: In this case-series study, PROM1 recessive variants were associated with early-onset, severe panretinal degeneration. The similar phenotypes observed in patients with homozygous missense variants and splice site variants compared with similarly aged patients with truncating variants suggests that all recessive variants have a null (or loss of function close to null) outcome on PROM1 function. In contrast, the dominant missense cases were associated with a milder, cone-driven phenotype, suggesting that the dominant disease is preferentially associated with cones. This has implications for the development of treatments for this severely blinding disease, and adeno-associated viral vector-based gene therapy and optogenetics could become successful treatment options.


Assuntos
Antígeno AC133/genética , Mutação/genética , Degeneração Retiniana/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Distrofias de Cones e Bastonetes/genética , DNA Recombinante/genética , Feminino , Genes Dominantes/genética , Genes Recessivos/genética , Variação Genética/genética , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Isoformas de Proteínas/genética , Estudos Retrospectivos , Transtornos da Visão/genética , Adulto Jovem
16.
Mol Med Rep ; 19(6): 4711-4718, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059048

RESUMO

Autosomal recessive cornea plana is a very rare hereditary ocular disease, characterized by a flattened corneal curvature, marked hyperopia due to low refractive power and frequently consequent accommodative esotropia. Other features include various cornea anterior segment abnormalities, without systemic problems. The purpose of the present study was to investigate the clinical and molecular alterations in a Chinese family with cornea plana. Full ophthalmic examinations of the patients were performed, including slit­lamp examination, fundus examination and ocular ultrasound. Whole­exome sequencing data were screened for pathological variants in the proband, which were confirmed by Sanger sequencing. One novel missense mutation, c.242A>G (p.N81S) and another novel 7 base­pair deletion mutation, c.772­779del (p.G258Cfs*30), were detected in the keratocan (KERA) gene; two affected siblings inherited these variations in a compound heterozygous state, which were derived from the clinically unaffected heterozygous father (c.772_779del) and mother (c.242A>G), respectively. Neither mutation was observed in unrelated healthy controls (n=200). Multiple computer software predictions supported the pathogenicity of the two variants. Furthermore, protein modeling prediction was performed to better understand the molecular basis of cornea plana, particularly the importance of the leucine­rich repeat domain. This study presents the 14th pathogenic KERA mutations identified worldwide and the first in East Asia so far, to the best of our knowledge. These findings guided prenatal diagnosis for the family in question and expand on the variant spectrum of KERA, therefore facilitating genetic counseling.


Assuntos
Doenças da Córnea/genética , Genes Recessivos/genética , Proteoglicanas/genética , Grupo com Ancestrais do Continente Asiático , Sequência de Bases , China , Córnea/anormalidades , Córnea/patologia , Doenças da Córnea/diagnóstico , Doenças da Córnea/patologia , Distrofias Hereditárias da Córnea/diagnóstico , Distrofias Hereditárias da Córnea/genética , Análise Mutacional de DNA , Éxons/genética , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Feminino , Humanos , Mutação de Sentido Incorreto , Linhagem , Análise de Sequência , Deleção de Sequência , Sequenciamento Completo do Exoma
17.
Hum Genet ; 138(6): 673-679, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31069506

RESUMO

The study of Mendelian diseases and the identification of their causative genes are of great significance in the field of genetics. The evaluation of the pathogenicity of genes and the total number of Mendelian disease genes are both important questions worth studying. However, very few studies have addressed these issues to date, so we attempt to answer them in this study. We calculated the gene pathogenicity prediction (GPP) score by a machine learning approach (random forest algorithm) to evaluate the pathogenicity of genes. When we applied the GPP score to the testing gene set, we obtained an accuracy of 80%, recall of 93% and area under the curve of 0.87. Our results estimated that a total of 10,384 protein-coding genes were Mendelian disease genes. Furthermore, we found the GPP score was positively correlated with the severity of disease. Our results indicate that GPP score may provide a robust and reliable guideline to predict the pathogenicity of protein-coding genes. To our knowledge, this is the first trial to estimate the total number of Mendelian disease genes.


Assuntos
Algoritmos , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença/genética , Aprendizado de Máquina , Genes Dominantes/genética , Genes Recessivos/genética , Doenças Genéticas Inatas/diagnóstico , Humanos , Curva ROC
18.
Am J Hum Genet ; 104(6): 1202-1209, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31079898

RESUMO

The wobble hypothesis was proposed to explain the presence of fewer tRNAs than possible codons. The wobble nucleoside position in the anticodon stem-loop undergoes a number of modifications that help maintain the efficiency and fidelity of translation. AlkB homolog 8 (ALKBH8) is an atypical member of the highly conserved AlkB family of dioxygenases and is involved in the formation of mcm5s2U, (S)-mchm5U, (R)-mchm5U, mcm5U, and mcm5Um at the anticodon wobble uridines of specific tRNAs. In two multiplex consanguineous families, we identified two homozygous truncating ALKBH8 mutations causing intellectual disability. Analysis of tRNA derived from affected individuals showed the complete absence of these modifications, consistent with the presumptive loss of function of the variants. Our results highlight the sensitivity of the brain to impaired wobble modification and expand the list of intellectual-disability syndromes caused by mutations in genes related to tRNA modification.


Assuntos
Homólogo AlkB 8 da RNAt Metiltransferase/genética , Códon/metabolismo , Genes Recessivos/genética , Deficiência Intelectual/etiologia , Mutação , RNA de Transferência/metabolismo , Uridina/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Códon/genética , Feminino , Humanos , Deficiência Intelectual/patologia , Masculino , RNA de Transferência/genética , Uridina/química , Uridina/genética , Adulto Jovem , tRNA Metiltransferases/metabolismo
19.
Int J Dermatol ; 58(8): 946-952, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31077348

RESUMO

BACKGROUND: Autosomal recessive wooly hair/hypotrichosis is an inherited disorder of hair characterized by less dense, short, and tightly curled hair on the scalp and sometimes less dense to complete absence of eyebrows and eyelashes. Autosomal recessive wooly hair/hypotrichosis phenotypes are mostly associated with pathogenic sequence variants in LIPH and LPAR6 genes. METHODS: To find out the molecular basis of the disease, five families with autosomal recessive wooly hair/hypotrichosis were recruited for genetic analysis. Direct Sanger sequencing of LIPH and LPAR6 genes was carried out using BigDye chain termination chemistry. P2RY5 protein homology models were developed to study the effect of mutation on protein structure in a family having novel mutation. RESULTS: Sanger sequencing revealed a novel homozygous missense mutation (c.47A>T) in the LPAR6 gene in family A, while recurrent mutation (c.436G>A) was detected in the rest of the four families (B-E). Protein homology models for both native and mutant P2RY5 protein were developed to study the difference in subtle structural features because of Lys16Met (K16M) mutation. We observed that P2RY5K16M mutation results decrease in the number of ionic interactions detrimental to the protein stability. Protein modeling studies revealed that the novel mutation identified here decreased the number of ionic interactions by affecting physicochemical parameters of the protein, leading to an overall decrease in protein stability with no major secondary structural changes. CONCLUSION: The molecular analysis further confirms the frequent involvement of LPAR6 in autosomal recessive wooly hair/hypotrichosis, while the bioinformatic study revealed that the missense mutation destabilizes the overall structure of P2RY5 protein.


Assuntos
Genes Recessivos/genética , Doenças do Cabelo/genética , Cabelo/anormalidades , Hipotricose/genética , Receptores de Ácidos Lisofosfatídicos/genética , Biologia Computacional , Consanguinidade , Feminino , Humanos , Masculino , Mutação de Sentido Incorreto , Paquistão , Linhagem , Fenótipo , Estrutura Secundária de Proteína/genética , Receptores de Ácidos Lisofosfatídicos/química , Receptores Purinérgicos P2/química , Receptores Purinérgicos P2/genética , Homologia de Sequência de Aminoácidos
20.
Genet Test Mol Biomarkers ; 23(6): 428-432, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081706

RESUMO

Background: Autosomal recessive congenital ichthyoses (ARCI) are a group of rare nonsyndromic genodermatoses characterized by generalized scaly appearance of the epidermis with markedly impaired cutaneous barriers owing to defects in keratinization related genes. In this study, we ascertained a consanguineous Pakistani family affected with ARCI. Aims: To investigate genetic defect underlying disease phenotype in the affected family. Methods: All available members of the family (affected and unaffected) were sampled. Whole exome sequencing (WES) was performed on DNA of the proband and the data were analyzed for probable pathogenic variants. Segregation of the identified variant was validated by Sanger sequencing. Results: Analysis of the WES data identified a novel nonsense mutation, c.762C>G, in the PNPLA1 (patatin-like phospholipase domain containing 1) gene. The protein product of of this gene is involved in lipid organization during cornified cell envelope formation. The variant is predicted to result in the generation of a premature truncation site at amino acid position 254 (p.Tyr254*). This would result in the loss of a large C-terminal portion of the protein suggesting it to be rendered nonfunctional. In silico protein structure modeling confirmed a detrimental effect of the variation on protein structure. Conclusions: The study supports the evidence for the prevalence of PNPLA1 mutations in distant ethnic groups. Despite the significant number of reported ARCI cases with PNPLA1 variants, a straightforward genotype-phenotype correlation cannot be established.


Assuntos
Ictiose Lamelar/genética , Lipase/genética , Adulto , Idoso , Códon sem Sentido/genética , Grupos Étnicos/genética , Família , Feminino , Genes Recessivos/genética , Humanos , Ictiose Lamelar/metabolismo , Lipase/fisiologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Paquistão , Linhagem , Fenótipo , Sequenciamento Completo do Exoma/métodos
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