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Homozygous variants in the HEXB and MBOAT7 genes underlie neurological diseases in consanguineous families.

ABSTRACT: BACKGROUND:Neurological disorders are a common cause of morbidity and mortality within Pakistani populations. It is one of the most important challenges in healthcare, with significant life-long socio-economic burden. METHODS:We investigated the cause of disease in three Pakistani families in individuals with unexplained autosomal recessive neurological conditions, using both genome-wide SNP mapping and whole exome sequencing (WES) of affected individuals. RESULTS:We identified a homozygous splice site variant (NM_000521:c.445?+?1G?>?T) in the hexosaminidase B (HEXB) gene confirming a diagnosis of Sandhoff disease (SD; type II GM2-gangliosidosis), an autosomal recessive lysosomal storage disorder caused by deficiency of hexosaminidases in a single family. In two further unrelated families, we identified a homozygous frameshift variant (NM_024298.3:c.758_778del; p.Glu253_Ala259del) in membrane-bound O-acyltransferase family member 7 (MBOAT7) as the likely cause of disease. MBOAT7 gene variants have recently been identified as a cause of intellectual disability (ID), seizures and autistic features. CONCLUSIONS:We identified two metabolic disorders of lipid biosynthesis within three Pakistani families presenting with undiagnosed neurodevelopmental conditions. These findings enabled an accurate neurological disease diagnosis to be provided for these families, facilitating disease management and genetic counselling within this population. This study consolidates variation within MBOAT7 as a cause of neurodevelopmental disorder, broadens knowledge of the clinical outcomes associated with MBOAT7-related disorder, and confirms the likely presence of a regionally prevalent founder variant (c.758_778del; p.Glu253_Ala259del) in Pakistan.

SUBMITTER: Khan S

PROVIDER: S-EPMC6921424 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Homozygous variants in the HEXB and MBOAT7 genes underlie neurological diseases in consanguineous families.

Khan Shazia S Rawlins Lettie E LE Harlalka Gaurav V GV Umair Muhammad M Ullah Asmat A Shahzad Shaheen S Javed Muhammad M Baple Emma L EL Crosby Andrew H AH Ahmad Wasim W Gul Asma A

BMC medical genetics 20191218 1

<h4>Background</h4>Neurological disorders are a common cause of morbidity and mortality within Pakistani populations. It is one of the most important challenges in healthcare, with significant life-long socio-economic burden.<h4>Methods</h4>We investigated the cause of disease in three Pakistani families in individuals with unexplained autosomal recessive neurological conditions, using both genome-wide SNP mapping and whole exome sequencing (WES) of affected individuals.<h4>Results</h4>We identi ...[more]

PMID: 31852446

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Project description:Introduction: Mucopolysaccharidoses are a group of lysosomal storage disorders that include seven types that are classified based on the enzymes that are disrupted. Malfunction of these enzymes leads to the accumulation of glycosaminoglycans (GAGs) in various tissues. Due to genetic and clinical heterogeneity, diagnosing and distinguishing the different types is challenging. Genetic methods such as whole exome sequencing (WES) and Sanger sequencing are accurate methods for detecting pathogenic variants in patients. Methods: Thirty-two cases of mucopolysaccharidosis, predominantly from families with consanguineous marriages, were genetically examined. Out of these, fourteen cases underwent targeted sequencing, while the rest underwent WES. The results of WES were analyzed and the pathogenicity of the variants was examined using bioinformatics tools. In addition, a segregation analysis within families was carried out. Results: In most cases, a pathogenic or likely pathogenic variant was detected. Sixteen previously reported variants and six new variants were detected in the known IDS (c.458G>C, c.701del, c.920T>G), GNS (c.1430A>T), GALNS (c.1218_1221dup), and SGSH (c.149T>C) genes. Furthermore, we discovered a c.259G>C substitution in the NAGLU gene for the first time in three homozygous patients. This substitution was previously reported as heterozygous. Except for the variants related to the IDS gene, which were hemizygous, all the other variants were homozygous. Discussion: It appears that the high rate of consanguineous marriages in the families being studied has had a significant impact on the occurrence of this disease. Overall, these findings could expand the spectrum of pathogenic variants in mucopolysaccharidoses. Genetic methods, especially WES, are very accurate and can be used alone or in conjunction with other diagnostic methods for a more precise and rapid diagnosis of mucopolysaccharidoses. Additionally, they could be beneficial for family screening and disease prevention.

Dataset Information

Homozygous variants in the HEXB and MBOAT7 genes underlie neurological diseases in consanguineous families.

Publications

Homozygous variants in the HEXB and MBOAT7 genes underlie neurological diseases in consanguineous families.

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