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1.
Am J Hum Genet ; 111(2): 338-349, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38228144

RESUMO

Clinical exome and genome sequencing have revolutionized the understanding of human disease genetics. Yet many genes remain functionally uncharacterized, complicating the establishment of causal disease links for genetic variants. While several scoring methods have been devised to prioritize these candidate genes, these methods fall short of capturing the expression heterogeneity across cell subpopulations within tissues. Here, we introduce single-cell tissue-specific gene prioritization using machine learning (STIGMA), an approach that leverages single-cell RNA-seq (scRNA-seq) data to prioritize candidate genes associated with rare congenital diseases. STIGMA prioritizes genes by learning the temporal dynamics of gene expression across cell types during healthy organogenesis. To assess the efficacy of our framework, we applied STIGMA to mouse limb and human fetal heart scRNA-seq datasets. In a cohort of individuals with congenital limb malformation, STIGMA prioritized 469 variants in 345 genes, with UBA2 as a notable example. For congenital heart defects, we detected 34 genes harboring nonsynonymous de novo variants (nsDNVs) in two or more individuals from a set of 7,958 individuals, including the ortholog of Prdm1, which is associated with hypoplastic left ventricle and hypoplastic aortic arch. Overall, our findings demonstrate that STIGMA effectively prioritizes tissue-specific candidate genes by utilizing single-cell transcriptome data. The ability to capture the heterogeneity of gene expression across cell populations makes STIGMA a powerful tool for the discovery of disease-associated genes and facilitates the identification of causal variants underlying human genetic disorders.


Assuntos
Cardiopatias Congênitas , Transcriptoma , Humanos , Animais , Camundongos , Exoma/genética , Cardiopatias Congênitas/genética , Sequenciamento do Exoma , Aprendizado de Máquina , Análise de Célula Única/métodos , Enzimas Ativadoras de Ubiquitina/genética
2.
Clin Genet ; 106(1): 47-55, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38378010

RESUMO

Skeletal dysplasias (SKDs) are a heterogeneous group of more than 750 genetic disorders characterized by abnormal development, growth, and maintenance of bones or cartilage in the human skeleton. SKDs are often caused by variants in early patterning genes and in many cases part of multiple malformation syndromes and occur in combination with non-skeletal phenotypes. The aim of this study was to investigate the underlying genetic cause of congenital SKDs in highly consanguineous Pakistani families, as well as in sporadic and familial SKD cases from India using multigene panel sequencing analysis. Therefore, we performed panel sequencing of 386 bone-related genes in 7 highly consanguineous families from Pakistan and 27 cases from India affected with SKDs. In the highly consanguineous families, we were able to identify the underlying genetic cause in five out of seven families, resulting in a diagnostic yield of 71%. Whereas, in the sporadic and familial SKD cases, we identified 12 causative variants, corresponding to a diagnostic yield of 44%. The genetic heterogeneity in our cohorts was very high and we were able to detect various types of variants, including missense, nonsense, and frameshift variants, across multiple genes known to cause different types of SKDs. In conclusion, panel sequencing proved to be a highly effective way to decipher the genetic basis of SKDs in highly consanguineous families as well as sporadic and or familial cases from South Asia. Furthermore, our findings expand the allelic spectrum of skeletal dysplasias.


Assuntos
Consanguinidade , Linhagem , Humanos , Masculino , Feminino , Paquistão/epidemiologia , Índia/epidemiologia , Osteocondrodisplasias/genética , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/patologia , Fenótipo , Criança , Mutação , Doenças do Desenvolvimento Ósseo/genética , Predisposição Genética para Doença , Pré-Escolar , Sequenciamento de Nucleotídeos em Larga Escala , Heterogeneidade Genética
4.
Hum Genet ; 138(6): 593-600, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30982135

RESUMO

Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.


Assuntos
Dedos/anormalidades , Genes Recessivos/genética , Predisposição Genética para Doença/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Polidactilia/genética , Dedos do Pé/anormalidades , Animais , Consanguinidade , Saúde da Família , Feminino , Dedos/patologia , Genótipo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Linhagem , Fenótipo , Polidactilia/patologia , Dedos do Pé/patologia , Sequenciamento do Exoma/métodos
5.
Genome Res ; 26(2): 183-91, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26755636

RESUMO

The CRISPR/Cas technology enables targeted genome editing and the rapid generation of transgenic animal models for the study of human genetic disorders. Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK. ZAK is a member of the MAPKKK family with no known role in limb development. We show that Zak is expressed in the developing limbs and that a CRISPR/Cas-mediated knockout of the two Zak isoforms is embryonically lethal in mice. In contrast, a deletion of the SAM domain induces a complex hindlimb defect associated with down-regulation of Trp63, a known split-hand/split-foot malformation disease gene. Our results identify ZAK as a key player in mammalian limb patterning and demonstrate the rapid utility of CRISPR/Cas genome editing to assign causality to human mutations in the mouse in <10 wk.


Assuntos
Deformidades Congênitas dos Membros/genética , MAP Quinase Quinase Quinases/genética , Proteínas Quinases/genética , Sequência de Aminoácidos , Animais , Proteínas de Bactérias , Proteína 9 Associada à CRISPR , Linhagem Celular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Técnicas de Cocultura , Endonucleases , Exoma , Feminino , Humanos , Escore Lod , MAP Quinase Quinase Quinases/química , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Linhagem , Polimorfismo de Nucleotídeo Único , Proteínas Quinases/química , Análise de Sequência de DNA
6.
Am J Med Genet A ; 176(2): 438-442, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29271569

RESUMO

Ciliopathies are disorders of the primary cilium that can affect almost all organs and that are characterized by pleiotropy and extensive intra- and interfamilial phenotypic variability. Accordingly, mutations in the same gene can cause different ciliopathy phenotypes of varying severity. WDR60 encodes a protein thought to play a role in the primary cilium's intraflagellar transport machinery. Mutations in this gene are a rare cause of Jeune asphyxiating thoracic dystrophy (JATD) and short-rib polydactyly syndrome (SRPS). Here we report on a milder and distinct phenotype in a consanguineous Pakistani pedigree with two adolescent sisters affected by retinal degeneration and postaxial polydactyly, but lack of any further skeletal or chondrodysplasia features. By targeted high-throughput sequencing of genes known or suspected to be involved in ciliogenesis, we detected a novel homozygous N-terminal truncating WDR60 mutation (c.44delC/p.Ala15Glufs*90) that co-segregated with the disease in the family. Our finding broadens the spectrum of WDR60-related phenotypes and shows the utility of broad multigene panels during the genetic work-up of patients with ciliopathies.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Polidactilia/genética , Degeneração Retiniana/genética , Síndrome de Costela Curta e Polidactilia/genética , Adolescente , Adulto , Cílios/genética , Cílios/patologia , Ciliopatias/genética , Ciliopatias/fisiopatologia , Síndrome de Ellis-Van Creveld/genética , Síndrome de Ellis-Van Creveld/fisiopatologia , Exoma/genética , Feminino , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Polidactilia/fisiopatologia , Degeneração Retiniana/fisiopatologia , Costelas/fisiopatologia , Síndrome de Costela Curta e Polidactilia/fisiopatologia , Irmãos , Adulto Jovem
7.
Hum Genet ; 136(11-12): 1455-1461, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29090338

RESUMO

Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of neurodevelopmental disorders with poor prognosis. Recent discoveries have greatly expanded the repertoire of genes that are mutated in epileptic encephalopathies and DEE, often in a de novo fashion, but in many patients, the disease remains molecularly uncharacterized. Here, we describe a new form of DEE in patients with likely deleterious biallelic variants in PTPN23. The phenotype is characterized by early onset drug-resistant epilepsy, severe and global developmental delay, microcephaly, and sometimes premature death. PTPN23 encodes a tyrosine phosphatase with strong brain expression, and its knockout in mouse is embryonically lethal. Structural modeling supports a deleterious effect of the identified alleles. Our data suggest that PTPN23 mutations cause a rare severe form of autosomal-recessive DEE in humans, a finding that requires confirmation.


Assuntos
Deficiências do Desenvolvimento/genética , Mutação , Proteínas Tirosina Fosfatases não Receptoras/genética , Espasmos Infantis/genética , Adulto , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Recém-Nascido , Masculino , Fenótipo , Conformação Proteica , Proteínas Tirosina Fosfatases não Receptoras/química , Espasmos Infantis/patologia
8.
Am J Hum Genet ; 93(3): 524-9, 2013 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-23932106

RESUMO

Epileptic encephalopathies are genetically heterogeneous severe disorders in which epileptic activity contributes to neurological deterioration. We studied two unrelated children presenting with a distinctive early-onset epileptic encephalopathy characterized by refractory epilepsy and absent developmental milestones, as well as thick and short corpus callosum and persistent cavum septum pellucidum on brain MRI. Using whole-exome sequencing, we identified biallelic mutations in seizure threshold 2 (SZT2) in both affected children. The causative mutations include a homozygous nonsense mutation and a nonsense mutation together with an exonic splice-site mutation in a compound-heterozygous state. The latter mutation leads to exon skipping and premature termination of translation, as shown by RT-PCR in blood RNA of the affected boy. Thus, all three mutations are predicted to result in nonsense-mediated mRNA decay and/or premature protein truncation and thereby loss of SZT2 function. Although the molecular role of the peroxisomal protein SZT2 in neuronal excitability and brain development remains to be defined, Szt2 has been shown to influence seizure threshold and epileptogenesis in mice, consistent with our findings in humans. We conclude that mutations in SZT2 cause a severe type of autosomal-recessive infantile encephalopathy with intractable seizures and distinct neuroradiological anomalies.


Assuntos
Alelos , Corpo Caloso/patologia , Predisposição Genética para Doença , Mutação/genética , Proteínas do Tecido Nervoso/genética , Espasmos Infantis/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Criança , Pré-Escolar , Feminino , Heterozigoto , Homozigoto , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Camundongos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/química , Linhagem
9.
Hum Genet ; 134(1): 45-51, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25218063

RESUMO

Holoprosencephaly is a clinically and genetically heterogeneous midline brain malformation associated with neurologic manifestations including developmental delay, intellectual disability and seizures. Although mutations in the sonic hedgehog gene SHH and more than 10 other genes are known to cause holoprosencephaly, many patients remain without a molecular diagnosis. Here we show that a homozygous truncating mutation of STIL not only causes severe autosomal recessive microcephaly, but also lobar holoprosencephaly in an extended consanguineous Pakistani family. STIL mutations have previously been linked to centrosomal defects in primary microcephaly at the MCPH7 locus. Our results thus expand the clinical phenotypes associated with biallellic STIL mutations to include holoprosencephaly.


Assuntos
Holoprosencefalia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Microcefalia/genética , Mutação/genética , Adolescente , Adulto , Pré-Escolar , Consanguinidade , Feminino , Humanos , Lactente , Masculino , Paquistão , Adulto Jovem
10.
Brain ; 137(Pt 4): 1107-19, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24613933

RESUMO

Dopamine transporter deficiency syndrome due to SLC6A3 mutations is the first inherited dopamine 'transportopathy' to be described, with a classical presentation of early infantile-onset progressive parkinsonism dystonia. In this study we have identified a new cohort of patients with dopamine transporter deficiency syndrome, including, most significantly, atypical presentation later in childhood with a milder disease course. We report the detailed clinical features, molecular genetic findings and in vitro functional investigations undertaken for adult and paediatric cases. Patients presenting with parkinsonism dystonia or a neurotransmitter profile characteristic of dopamine transporter deficiency syndrome were recruited for study. SLC6A3 mutational analysis was undertaken in all patients. The functional consequences of missense variants on the dopamine transporter were evaluated by determining the effect of mutant dopamine transporter on dopamine uptake, protein expression and amphetamine-mediated dopamine efflux using an in vitro cellular heterologous expression system. We identified eight new patients from five unrelated families with dopamine transporter deficiency syndrome. The median age at diagnosis was 13 years (range 1.5-34 years). Most significantly, the case series included three adolescent males with atypical dopamine transporter deficiency syndrome of juvenile onset (outside infancy) and progressive parkinsonism dystonia. The other five patients in the cohort presented with classical infantile-onset parkinsonism dystonia, with one surviving into adulthood (currently aged 34 years) and labelled as having 'juvenile parkinsonism'. All eight patients harboured homozygous or compound heterozygous mutations in SLC6A3, of which the majority are previously unreported variants. In vitro studies of mutant dopamine transporter demonstrated multifaceted loss of dopamine transporter function. Impaired dopamine uptake was universally present, and more severely impacted in dopamine transporter mutants causing infantile-onset rather than juvenile-onset disease. Dopamine transporter mutants also showed diminished dopamine binding affinity, reduced cell surface transporter, loss of post-translational dopamine transporter glycosylation and failure of amphetamine-mediated dopamine efflux. Our data series expands the clinical phenotypic continuum of dopamine transporter deficiency syndrome and indicates that there is a phenotypic spectrum from infancy (early onset, rapidly progressive disease) to childhood/adolescence and adulthood (later onset, slower disease progression). Genotype-phenotype analysis in this cohort suggests that higher residual dopamine transporter activity is likely to contribute to postponing disease presentation in these later-onset adult cases. Dopamine transporter deficiency syndrome remains under-recognized and our data highlights that dopamine transporter deficiency syndrome should be considered as a differential diagnosis for both infantile- and juvenile-onset movement disorders, including cerebral palsy and juvenile parkinsonism.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/deficiência , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Estudos de Associação Genética , Transtornos dos Movimentos/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Immunoblotting , Lactente , Masculino , Transtornos dos Movimentos/complicações , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Adulto Jovem
11.
Am J Hum Genet ; 88(2): 127-37, 2011 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-21255762

RESUMO

By using homozygosity mapping in a consanguineous Pakistani family, we detected linkage of nonsyndromic hearing loss to a 7.6 Mb region on chromosome 3q13.31-q21.1 within the previously reported DFNB42 locus. Subsequent candidate gene sequencing identified a homozygous nonsense mutation (c.1135G>T [p.Glu379X]) in ILDR1 as the cause of hearing impairment. By analyzing additional consanguineous families with homozygosity at this locus, we detected ILDR1 mutations in the affected individuals of 10 more families from Pakistan and Iran. The identified ILDR1 variants include missense, nonsense, frameshift, and splice-site mutations as well as a start codon mutation in the family that originally defined the DFNB42 locus. ILDR1 encodes the evolutionarily conserved immunoglobulin-like domain containing receptor 1, a putative transmembrane receptor of unknown function. In situ hybridization detected expression of Ildr1, the murine ortholog, early in development in the vestibule and in hair cells and supporting cells of the cochlea. Expression in hair cell- and supporting cell-containing neurosensory organs is conserved in the zebrafish, in which the ildr1 ortholog is prominently expressed in the developing ear and neuromasts of the lateral line. These data identify loss-of-function mutations of ILDR1, a gene with a conserved expression pattern pointing to a conserved function in hearing in vertebrates, as underlying nonsyndromic prelingual sensorineural hearing impairment.


Assuntos
Códon sem Sentido/genética , Genes Recessivos/genética , Predisposição Genética para Doença , Perda Auditiva/genética , Receptores de Superfície Celular/genética , Animais , Mapeamento Cromossômico , Cromossomos Humanos Par 3/genética , Consanguinidade , Orelha Interna , Feminino , Ligação Genética , Genótipo , Humanos , Hibridização In Situ , Escore Lod , Masculino , Camundongos , Linhagem , Peixe-Zebra
12.
Mol Biol Rep ; 41(2): 1103-7, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24390236

RESUMO

CHEK2 encodes a serine/threonine-protein kinase which plays a critical role in DNA damage signaling pathways. CHEK2 directly phosphorylates and regulates the functions of p53 and BRCA1. Most women with breast and/or ovarian cancer are not carriers of mutant BRCA1 or BRCA2. Multiple studies have shown that a CHEK2*1100delC confers about a two-fold increased risk of breast cancer in unselected females and a tenfold increase in males. Moreover, studies have shown that first-degree relatives of bilateral breast cancer cases who carried the CHEK2*1100delC allele had an eight-fold increased risk of breast cancer. It has been suggested that CHEK2 functions as a low-penetrance susceptibility gene for cancers and multiplies the risks associated with other gene(s) to increase cancer risk. The main goal of this study was to evaluate and to compare the role of truncating mutations, splice junction mutations and rare missense substitutions in breast cancer susceptibility gene CHEK2. Present study was performed on 140 individuals including 70 breast cancer patients both with and without family history and 70 normal individuals. Written consent was obtained and 3 ml intravenous blood was drawn from all the subjects. DNA was extracted from all the samples through inorganic method published already. Primers were synthesized for all the 14 exons of CHEK2 gene. Coding and adjacent intronic sequences of CHEK2 gene were amplified and sequenced. Two genetic variants (p.H371Y, p.D438Y) were found in exon 10 and exon 11 of gene CHEK2 which were not found in any of the 70 control individuals from same geographical area and ethnic group. The genetic variant c.1312G>T (p.D438Y) identified in a patient with a family history of breast cancer. To our knowledge, this is first mutation scanning study of gene CHEK2 from Balochistan population.


Assuntos
Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Neoplasias da Mama/patologia , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Fatores de Risco
13.
Sci Rep ; 14(1): 16302, 2024 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-39009627

RESUMO

Androgen insensitivity syndrome (AIS) is a difference of sex development (DSD) characterized by different degrees of undervirilization in individuals with a 46,XY karyotype despite normal to high gonadal testosterone production. Classically, AIS is explained by hemizygous mutations in the X-chromosomal androgen receptor (AR) gene. Nevertheless, the majority of individuals with clinically diagnosed AIS do not carry an AR gene mutation. Here, we present a patient with a 46,XY karyotype, born with undervirilized genitalia, age-appropriate testosterone levels and no uterus, characteristic for AIS. Diagnostic whole exome sequencing (WES) showed a maternally inherited LINE1 (L1) retrotransposon insertion in the 5' untranslated region (5'UTR) of the AR gene. Long-read nanopore sequencing confirmed this as an insertion of a truncated L1 element of ≈ 2.7 kb and showed an increased DNA methylation at the L1 insertion site in patient-derived genital skin fibroblasts (GSFs) compared to healthy controls. The insertion coincided with reduced AR transcript and protein levels in patient-derived GSFs confirming the clinical diagnosis AIS. Our results underline the relevance of retrotransposons in human disease, and expand the growing list of human diseases associated with them.


Assuntos
Síndrome de Resistência a Andrógenos , Metilação de DNA , Epigênese Genética , Elementos Nucleotídeos Longos e Dispersos , Receptores Androgênicos , Humanos , Síndrome de Resistência a Andrógenos/genética , Síndrome de Resistência a Andrógenos/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Masculino , Elementos Nucleotídeos Longos e Dispersos/genética , Feminino , Sequenciamento do Exoma , Transcrição Gênica
14.
Nat Genet ; 56(6): 1080-1089, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38684900

RESUMO

Despite linkage to chromosome 16q in 1996, the mutation causing spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, remained unknown. Here, using long-read single-strand whole-genome sequencing (LR-GS), we identified a heterozygous GGC-repeat expansion in a large Utah pedigree encoding polyglycine (polyG) in zinc finger homeobox protein 3 (ZFHX3), also known as AT-binding transcription factor 1 (ATBF1). We queried 6,495 genome sequencing datasets and identified the repeat expansion in seven additional pedigrees. Ultrarare DNA variants near the repeat expansion indicate a common distant founder event in Sweden. Intranuclear ZFHX3-p62-ubiquitin aggregates were abundant in SCA4 basis pontis neurons. In fibroblasts and induced pluripotent stem cells, the GGC expansion led to increased ZFHX3 protein levels and abnormal autophagy, which were normalized with small interfering RNA-mediated ZFHX3 knockdown in both cell types. Improving autophagy points to a therapeutic avenue for this novel polyG disease. The coding GGC-repeat expansion in an extremely G+C-rich region was not detectable by short-read whole-exome sequencing, which demonstrates the power of LR-GS for variant discovery.


Assuntos
Autofagia , Proteínas de Homeodomínio , Linhagem , Ataxias Espinocerebelares , Expansão das Repetições de Trinucleotídeos , Humanos , Autofagia/genética , Expansão das Repetições de Trinucleotídeos/genética , Proteínas de Homeodomínio/genética , Ataxias Espinocerebelares/genética , Masculino , Feminino , Células-Tronco Pluripotentes Induzidas/metabolismo
15.
Am J Med Genet A ; 161A(4): 884-8, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23436491

RESUMO

The Say-Barber/Biesecker/Young-Simpson (SBBYS) type of the blepharophimosis-mental retardation syndrome group (Ohdo-like syndromes) is a multiple congenital malformation syndrome characterized by vertical narrowing and shortening of the palpebral fissures, ptosis, intellectual disability, hypothyroidism, hearing impairment, and dental anomalies. Mutations of the gene encoding the histone-acetyltransferase KAT6B have been recently identified in individuals affected by SBBYS syndrome. SBBYS syndrome-causing KAT6B mutations cluster in a ~1,700 basepair region in the 3' part of the large exon 18, while mutations located in the 5' region of the same exon have recently been identified to cause the genitopatellar syndrome (GPS), a clinically distinct although partially overlapping malformation-intellectual disability syndrome. Here, we present two children with clinical features of SBBYS syndrome and de novo truncating KAT6B mutations, including a boy who was diagnosed at the age of 4 months. Our results confirm the implication of KAT6B mutations in typical SBBYS syndrome and emphasize the importance of genotype-phenotype correlations at the KAT6B locus where mutations truncating the KAT6B protein at the amino-acid positions ~1,350-1,920 cause SBBYS syndrome.


Assuntos
Blefarofimose/genética , Hipotireoidismo Congênito/genética , Cardiopatias Congênitas/genética , Histona Acetiltransferases/genética , Deficiência Intelectual/genética , Instabilidade Articular/genética , Mutação , Anormalidades Múltiplas , Sequência de Bases , Blefarofimose/diagnóstico , Pré-Escolar , Hibridização Genômica Comparativa , Hipotireoidismo Congênito/diagnóstico , Éxons , Fácies , Feminino , Estudos de Associação Genética , Cardiopatias Congênitas/diagnóstico , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Instabilidade Articular/diagnóstico , Cariótipo , Masculino , Fenótipo
16.
Hum Genome Var ; 10(1): 16, 2023 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-37221169

RESUMO

Split-hand/foot malformation (SHFM) shows diverse heterogeneity and manifests with reduced penetrance and variable expressivity. This study investigated the underlying genetic cause of a family segregating SHFM. Exome sequencing followed by Sanger sequencing identified a novel single nucleotide heterozygous variant (NC_000019.9 (NM_005499.3):c.1118del) in UBA2 cosegregating in the family in an autosomal dominant manner. Our findings conclude that reduced penetrance and variable expressivity are the two remarkable and unusual features of SHFM.

17.
Front Neurol ; 14: 1168307, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37305761

RESUMO

Introduction: Intellectual disability (ID) is a clinically and genetically heterogeneous disorder. It drastically affects the learning capabilities of patients and eventually reduces their IQ level below 70. Methods: The current genetic study ascertained two consanguineous Pakistani families suffering from autosomal recessive intellectual developmental disorder-5 (MRT5). We have used exome sequencing followed by Sanger sequencing to identify the disease-causing variants. Results and discussion: Genetic analysis using whole exome sequencing in these families identified two novel mutations in the NSUN2 (NM_017755.5). Family-A segregated a novel missense variant c.953A>C; p.Tyr318Ser in exon-9 of the NSUN2. The variant substituted an amino acid Tyr318, highly conserved among different animal species and located in the functional domain of NSUN2 known as "SAM-dependent methyltransferase RsmB/NOP2-type". Whereas in family B, we identified a novel splice site variant c.97-1G>C that affects the splice acceptor site of NSUN2. The identified splice variant (c.97-1G>C) was predicted to result in the skipping of exon-2, which would lead to a frameshift followed by a premature stop codon (p. His86Profs*16). Furthermore, it could result in the termination of translation and synthesis of dysfunctional protein, most likely leading to nonsense-mediated decay. The dynamic consequences of NSUN2 missense variant was further explored together with wildtype through molecular dynamic simulations, which uncovered the disruption of NSUN2 function due to a gain in structural flexibility. The present molecular genetic study further extends the mutational spectrum of NSUN2 to be involved in ID and its genetic heterogeneity in the Pakistani population.

18.
Hum Genet ; 131(2): 209-16, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21761136

RESUMO

We performed homozygosity mapping in a consanguineous Pakistani family segregating autosomal-recessive congenital cataracts and identified linkage to a 3.03 Mb locus on chromosome 6p24 containing the GCNT2 gene. GCNT2 encodes glucosaminyl (N-acetyl) transferase 2, an enzyme responsible for the formation of the blood group I antigen. Rare biallelic GCNT2 mutations have been shown to cause the association of congenital cataracts and the adult i blood group, making GCNT2 the prime candidate gene for the observed phenotype. Indeed, we identified a homozygous deletion segregating with cataracts that encompasses exons 1B, 1C, 2 and 3 of GCNT2. Long-range polymerase chain reaction and breakpoint sequencing revealed that affected individuals in this and in a second, apparently unrelated Pakistani family segregating congenital cataracts are homozygous for the same 93 kb deletion. The deletion is flanked by Alu repeats of the AluS family on both sides and microsatellite genotyping suggested that its occurrence in the two families was the product of recurrent Alu-Alu repeat-mediated nonhomologous recombinations or an old founder effect. Subsequently, we showed that cataract-affected individuals in both families have the adult i blood group, whereas unaffected individuals have blood group I as the vast majority of the population. Because the GCNT2 locus is rich in Short INterspersed Elements (SINE repeats) and thus likely prone to genomic rearrangements, microdeletions or microduplications at this locus might cause a larger than currently anticipated fraction of apparently isolated autosomal-recessive cataracts.


Assuntos
Elementos Alu , Antígenos de Grupos Sanguíneos/genética , Catarata/congênito , Catarata/genética , N-Acetilglucosaminiltransferases/genética , Deleção de Sequência , Sequência de Bases , Consanguinidade , Feminino , Ligação Genética , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
19.
Mol Biol Rep ; 39(5): 6197-201, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22219087

RESUMO

Canavan disease (OMIM 271900) is an autosomal recessive lethal neurodegenerative disorder characterized by spongy degeneration of the brain. A highly consanguineous Pakistani family with Canavan disease was enrolled on the basis of diagnosis. All the affected individuals have mental retardation, megalocephaly and degradation of motor skills, poor head control, partial vision loss, weakness of the muscles and raised urinary concentration of N-acetyl aspartic acid in the urine. Blood samples were collected from affected as well as normal siblings and processed for DNA purification. Linkage analysis was performed by typing three short tandem repeat markers D17S1583 (7.19 cM), D17S1828 (10.02 cM) and D17S919 (14.69 cM) for an already-reported gene/locus ASPA at chromosome 17p13.2 causing Canavan disease. During linkage analysis, all the affected individuals were homozygous for short tandem repeat markers while the normal siblings were heterozygous showing co-segregation of the disease. Gene ASPA (NM_000049) was undertaken to sequence for mutation analysis. As a result of sequence analysis, we found missense substitution 740A→G (p.G274R) in exon 6 of gene ASPA. To our knowledge, this is the first report about Canavan disease on a Pakistani family.


Assuntos
Amidoidrolases/genética , Doença de Canavan/enzimologia , Doença de Canavan/genética , Mutação de Sentido Incorreto/genética , Adolescente , Sequência de Bases , Criança , Análise Mutacional de DNA , Família , Feminino , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Paquistão , Linhagem , Adulto Jovem
20.
Mol Vis ; 17: 1940-5, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21850168

RESUMO

PURPOSE: To determine the cause of Leber congenital amaurosis (LCA) and developmental cataracts in a consanguineous Pakistani family. METHODS: The diagnosis was established in all affected individuals of a Pakistani LCA family by medical history, funduscopy, and standard ERG. We performed genome-wide linkage analysis for mapping the disease locus in this family. RESULTS: Congenitally severely reduced visual acuity and nystagmus were reported for all patients who, in the later phase of the disease, also developed cataracts. LCA in the family cosegregated with homozygosity for a single nucleotide polymorphism (SNP) haplotype on chromosome 6p14.1. The respective candidate region contained Leber congenital amaurosis 5 (LCA5), a gene previously reported to underlie LCA. We subsequently identified a novel truncating mutation in exon 4 of LCA5, c.642delC, in homozygous state in all affected persons of the family. CONCLUSIONS: We report a novel LCA5 mutation causing LCA in a Pakistani family. Developmental cataracts were present in two of the four patients, raising the possibility that LCA5 mutations may predispose to this additional ocular pathology.


Assuntos
Catarata/genética , Proteínas do Olho , Olho/metabolismo , Amaurose Congênita de Leber/genética , Proteínas Associadas aos Microtúbulos , Nistagmo Congênito/genética , Adolescente , Povo Asiático/genética , Sequência de Bases , Catarata/complicações , Catarata/fisiopatologia , Criança , Consanguinidade , Análise Mutacional de DNA , Éxons , Olho/fisiopatologia , Proteínas do Olho/genética , Feminino , Ligação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Homozigoto , Humanos , Amaurose Congênita de Leber/complicações , Amaurose Congênita de Leber/fisiopatologia , Masculino , Proteínas Associadas aos Microtúbulos/genética , Dados de Sequência Molecular , Mutação , Nistagmo Congênito/complicações , Nistagmo Congênito/fisiopatologia , Paquistão , Linhagem , Polimorfismo de Nucleotídeo Único
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