Whole-Exome Sequencing of Pakistani Consanguineous Families Identified Pathogenic Variants in Genes of Intellectual Disability

Abstract

Intellectual disability (ID) is a condition of significant limitation of cognitive functioning and adaptive behavior, with 50% of etiology attributed to genetic predisposition. We recruited two consanguineous Pakistani families manifesting severe ID and developmental delay. The probands were subjected to whole exome sequencing (WES) and variants were further prioritized based on population frequency, predicted pathogenicity and functional relevance. The WES data analysis identified homozygous pathogenic variants in genes MBOAT7 and TRAPPC9. The pathogenicity of the variants was supported by co-segregation analysis and in silico tool. The findings of this study expand mutation spectrum and provide additional evidence to the role of MBOAT7 and TRAPPC9 in causation of ID.

Exome sequencing identifies homozygous variants in MBOAT7 associated with neurodevelopmental disorder

“…Johansen et al identified biallelic loss‐of‐function mutations in MBOAT7 as the cause of autosmal recessive intellectual disability (ARID) 12 . Prior research also has demonstrated that individuals with biallelic mutations in the MBOAT7 gene exhibit ID, microcephaly, delayed motor milestone acquisition, seizures, speech difficulty, and occasionally autistic features 4,7,10 . In our patients, the identified variants resides in the fifth domain of the MBOAT7 and is associated with features including ID, microcephaly, aggressive behavior, febrile seizure, and global developmental delay presenting symptoms overlapping with the aforementioned reported patients.…”

“…12 Prior research also has demonstrated that individuals with biallelic mutations in the MBOAT7 gene exhibit ID, microcephaly, delayed motor milestone acquisition, seizures, speech difficulty, and occasionally autistic features. 4,7,10 In our patients, the identified variants resides in the fifth domain of the…”

“…Using advanced technology (exome sequencing), novel homozygous missense variants (NM_024298.5: c.588G > T; Trp196Cys, c.736T > C; Tyr246His and c.524A > C; p.Asp175Ala) and rare homozygous in-frame deletion variants (c.758_778del;p.Glu253_Ala259del) in MBOAT7 gene were identified previously described to cause similar NDD phenotypes. 4 To date, twenty-three disease-causing variants in MBOAT7 have been associated with heterogeneous clinical features such as moderate to severe ID, epilepsy, developmental delay, attention-deficit hyperactivity disorder (ADHD), microcephaly or macrocephaly, and autistic features 6,10 (Supplementary Table S1). Out of these 23 disease-causing variants in the MBOAT7, 10 were missense, 2 splicing site, 10 frameshifts, and 1 repeat pathogenic variants listed within the Human Gene Mutation Database (HGMD, http://www.hgmd.…”

“…MBOAT7 is localized in the endoplasmic reticulum, mitochondria-associated membrane and lipid droplets, which play vital roles during the process of hepatic phospholipid remodeling and a noncanonical hepatic triglyceride synthesis pathway. 4,10 Cells remodel glycerophospholipid acyl chains via the Lands cycle to adjust membrane properties. MBOAT7 acylates lyso-phosphatidylinositol (lyso-PI)…”

“…The MBOAT7 gene, also known as BB1; LRC4; LENG4; LPIAT; LPLAT; MBOA7; MRT57; OACT7; LPIAT1; LPLAT11 ; and hMBOA‐7 , is composed of 8 exons encoding a 472 amino acids protein (NP_077274.3) of total mass 52 765 (Da) and is located on chromosome 19q13.42. MBOAT7 is localized in the endoplasmic reticulum, mitochondria‐associated membrane and lipid droplets, which play vital roles during the process of hepatic phospholipid remodeling and a noncanonical hepatic triglyceride synthesis pathway 4,10 . Cells remodel glycerophospholipid acyl chains via the Lands cycle to adjust membrane properties.…”