RESUMO
Pediatric cardiomyopathies are mostly attributed to variants in sarcomere-related genes. Unfortunately, the genetic architecture of pediatric cardiomyopathies has never been previously studied in Jordan. We sought to uncover the genetic landscape of 14 patients from nine families with several subtypes of pediatric cardiomyopathies in Jordan using Exome sequencing (ES). Our investigation identified pathogenic and likely pathogenic variants in seven out of nine families (77.8%), clustering in sarcomere-related genes. Surprisingly, phenocopies of sarcomere-related hypertrophic cardiomyopathies were evident in probands with glycogen storage disorder and mitochondrial-related disease. Our study underscored the significance of streamlining ES or expanding cardiomyopathy-related gene panels to identify plausible phenocopies of sarcomere-related cardiomyopathies. Our findings also pointed out the need for genetic testing in patients with cardiomyopathy and their at-risk family members. This can potentially lead to better management strategies, enabling early interventions, and ultimately enhancing their prognosis. Finally, our findings provide an initial contribution to the currently absent knowledge about the molecular underpinnings of cardiomyopathies in Jordan.
Assuntos
Cardiomiopatias , Linhagem , Sarcômeros , Humanos , Jordânia , Masculino , Feminino , Sarcômeros/genética , Criança , Cardiomiopatias/genética , Cardiomiopatias/diagnóstico , Pré-Escolar , Sequenciamento do Exoma , Lactente , Fenótipo , Adolescente , Mutação , Testes Genéticos/métodosAssuntos
Proteína do Grupo de Complementação A da Anemia de Fanconi , Anemia de Fanconi , Mutação , Fenótipo , Irmãos , Humanos , Anemia de Fanconi/genética , Anemia de Fanconi/diagnóstico , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Masculino , Feminino , Predisposição Genética para Doença , Análise Mutacional de DNA , Pele/patologia , CriançaRESUMO
Biliary atresia (BA) is a progressive inflammatory process of the biliary tree resulting in biliary obstruction. No single known genetic or environmental factor has been established to cause BA. Cystic fibrosis (CF) is a rare cause of neonatal cholestasis, and it has never been described in familial BA cases. Here, we investigate two siblings of first-degree consanguineous parents presenting with neonatal BA. Shortly after the Kasai operation, the proband developed severe respiratory symptoms attributable to a missed CF diagnosis. This was discovered after re-investigating the family history, which revealed a first-degree cousin with CF who did not manifest BA. Afterwards, we identified a pathogenic variant (DeltaF508) in CFTR in both BA-affected siblings along with their cousin. This intrigued us to study the molecular etiology behind the familial BA presentations, which exclusively contributed to BA-pathogenesis in BA-CF-affected siblings and not in their CF-only affected cousin. We applied a multistep approach to investigate the variant profile of both siblings' and their cousin's exomes. We curated the genes whose variants were shared by the BA-CF siblings but absent or heterozygous in their CF-only-affected cousin. Consequently, we identified three candidate genes (SNAPC4, UCK1, and ZHX2) besides CFTR. We propose that these genes act cumulatively or individually in inducing BA-pathogenesis-either by aggravating the biliary damage in the context of CF or increasing the susceptibility of BA as a separate CF-comorbidity. To our knowledge, this is the first report of DeltaF508 in CFTR with familial neonatal BA cases.
Assuntos
Atresia Biliar , Fibrose Cística , Humanos , Recém-Nascido , Fibrose Cística/genética , Fibrose Cística/diagnóstico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Atresia Biliar/genética , Perfil Genético , Mutação , Fatores de Transcrição/genética , Proteínas de Homeodomínio/genéticaRESUMO
SLC26A4 is one of the most common genes causing autosomal recessive non-syndromic sensorineural hearing loss (SNHL). It has been reported to cause Pendred Syndrome (PDS) and DFNB4 which is deafness with enlarged vestibular aqueduct (EVA). However, mutated SLC26A4 is not conclusive for having either DFNB4 or PDS. Three unrelated Jordanian families consisting of eight affected individuals with congenital bilateral hearing loss (HL) participated in this study. Whole-exome and Sanger sequencing were performed to investigate the underlying molecular etiology of HL. Further clinical investigations, including laboratory blood workup for the thyroid gland, CT scan for the temporal bone, and thyroid ultrasound were performed. Three disease-causing variants were identified in SLC26A4 in the three families, two of which were novel. Two families had a novel pathogenic homozygous splice-site accepter variant (c.165-1G>C), while the third family had compound heterozygous pathogenic variants (c.1446G>A; p.Trp482* and c.304G>A; p.Gly102Arg). Our approach helped in redirecting the diagnosis of several affected members of three different families from non-syndromic HL to syndromic HL. Two of the affected individuals had typical PDS, one had DFNB4, while the rest had atypical PDS. Our work emphasized the intra- and inter-familial variability of SLC26A4-related phenotypes. In addition, we highlighted the variable phenotypic impact of SLC26A4 on tailoring a personalized healthcare management.
Assuntos
Perda Auditiva Neurossensorial , Proteínas de Membrana Transportadoras , Humanos , Mutação , Proteínas de Membrana Transportadoras/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Variação Biológica da População , Transportadores de Sulfato/genéticaRESUMO
Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral disease characterized by progressive neurodegeneration with variable involvement of multisystemic abnormalities. Crohn's disease (CD) is an inflammatory bowel disease (IBD) with a multifactorial etiology influenced by variants in NOD2. Here, we investigated a patient with plausible multisystemic overlapping manifestations of both NPC and CD. Her initial hospitalization was due to a prolonged fever and non-bloody diarrhea. A few months later, she presented with recurrent skin tags and anal fissures. Later, her neurological and pulmonary systems progressively deteriorated, leading to her death at the age of three and a half years. Differential diagnosis of her disease encompassed a battery of clinical testing and genetic investigations. The patient's clinical diagnosis was inconclusive. Specifically, the histopathological findings were directed towards an IBD disease. Nevertheless, the diagnosis of IBD was not consistent with the patient's subsequent neurological and pulmonary deterioration. Consequently, we utilized a genetic analysis approach to guide the diagnosis of this vague condition. Our phenotype-genotype association attempts led to the identification of candidate disease-causing variants in both NOD2 and NPC1. In this study, we propose a potential composite digenic impact of these two genes as the underlying molecular etiology. This work lays the foundation for future functional and mechanistic studies to unravel the digenic role of NOD2 and NPC1.
Assuntos
Doença de Crohn , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C , Proteína Adaptadora de Sinalização NOD2 , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Feminino , Estudos de Associação Genética , Testes Genéticos , Humanos , Proteína C1 de Niemann-Pick/genética , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/patologia , Proteína Adaptadora de Sinalização NOD2/genéticaRESUMO
Variants in Tbox transcription factor 5 (TBX5) can result in a wide phenotypic spectrum, specifically in the heart and the limbs. TBX5 has been implicated in causing nonsyndromic cardiac defects and HoltOram syndrome (HOS). The present study investigated the underlying molecular etiology of a family with heterogeneous heart defects. The proband had mixedtype total anomalous pulmonary venous return (mixedtype TAPVR), whereas her mother had an atrial septal defect. Genetic testing through triobased wholeexome sequencing was used to reveal the molecular etiology. A nonsense variant was identified in TBX5 (c.577G>T; p.Gly193*) initially showing cosegregation with a presumably nonsyndromic presentation of congenital heart disease. Subsequent genetic investigations and more complete phenotyping led to the correct diagnosis of HOS, documenting the novel association of mixedtype TAPVR with HOS. Finally, protein modeling of the mutant TBX5 protein that harbored this pathogenic nonsense variant (p.Gly193*) revealed a substantial drop in the quantity of noncovalent bonds. The decrease in the number of noncovalent bonds suggested that the resultant mutant dimer was less stable compared with the wildtype protein, consequently affecting the protein's ability to bind DNA. The present findings extended the phenotypic cardiac defects associated with HOS; to the best of our knowledge, this is the first association of mixedtype TAPVR with TBX5. Prior to the current analysis, the molecular association of TAPVR with HOS had never been documented; hence, this is the first genetic investigation to report the association between TAPVR and HOS. Furthermore, it was demonstrated that the nullvariants reported in the Tbox domain of TBX5 were associated with a wide range of cardiac and/or skeletal anomalies on both the interand intrafamilial levels. In conclusion, genetic testing was highlighted as a potentially powerful approach in the prognostication of the proper diagnosis.
Assuntos
Cardiopatias Congênitas , Comunicação Interatrial , Síndrome de Cimitarra , Proteínas com Domínio T , Anormalidades Múltiplas , Feminino , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Comunicação Interatrial/diagnóstico , Comunicação Interatrial/genética , Humanos , Deformidades Congênitas das Extremidades Inferiores , Fenótipo , Síndrome de Cimitarra/genética , Proteínas com Domínio T/genética , Deformidades Congênitas das Extremidades SuperioresRESUMO
Whole Exome Sequencing (WES) is a powerful approach for detecting sequence variations in the human genome. The aim of this study was to investigate the genetic defects in Jordanian patients with inherited retinal dystrophies (IRDs) using WES. WES was performed on proband patients' DNA samples from 55 Jordanian families. Sanger sequencing was used for validation and segregation analysis of the detected, potential disease-causing variants (DCVs). Thirty-five putatively causative variants (6 novel and 29 known) in 21 IRD-associated genes were identified in 71% of probands (39 of the 55 families). Three families showed phenotypes different from the typically reported clinical findings associated with the causative genes. To our knowledge, this is the largest genetic analysis of IRDs in the Jordanian population to date. Our study also confirms that WES is a powerful tool for the molecular diagnosis of IRDs in large patient cohorts.