Description of novel variants in consanguineous Pakistani families affected with intellectual disability.

BACKGROUND: Intellectual disability (ID) is a neurodevelopmental condition, affecting 1-3% of the population. Genetic factors play a key role causing the limitation in intellectual functioning and adaptive behavior. The heterogeneity of ID makes it more difficult for genetic and clinical diagnosis. Mapping of variants through next generation DNA sequencing in consanguineous families would help to understand the molecular parthenogenesis of ID. OBJECTIVE: The aim of this study was to describe the genetic variants of ID in consanguineous Pakistani families. METHODS: We analyzed four unrelated consanguineous Pakistani families having an intellectual disability through whole exome sequencing (WES). Data was analyzed using different bioinformatics tools and software. RESULTS: We mapped four novel variants in different ID genes. Each variant is found in different family, co-segregating with a recessive pattern of inheritance. The variants found are; c.1437delG:p.Asn480Thrfs*10, mapped in FKRP, c.2041 C>A:p.Leu681Met in HIRA, c.382 C>T:p.Arg128Cys in BDH1 and c.267+1G>A:p.? identified in TRAPPC6B. CONCLUSIONS: These variants help in demonstration of status and molecular basis of intellectual disability in Pakistani population leading to provision of genetic counseling services and a contribution in disease variant database.

Whole exome sequencing revealed novel variants in consanguineous Pakistani families with intellectual disability.

BACKGROUND: Intellectual disability (ID) is a heterogeneous disorder affecting 1-3% of the population. Elucidation of monogenic variants for ID is a current challenge. These variants can be better demonstrated in consanguineous affected families. OBJECTIVE: The study was designed to find the genetic variants of ID in consanguineous families. METHODS: We analyzed five unrelated consanguineous Pakistani families affected with ID using whole exome sequencing (WES). Data was analyzed using different bioinformatics tools and software. RESULTS: We mapped four variants including three novels in four different ID known genes. Each variant is found in a different family, co-segregating with a recessive pattern of inheritance. The novel variants found are; c. 2_4del (p.?) mapped in ROS1 and c. 718G>A (p.Gly240Arg) in GRM1. Another novel causative variant, c.2673del (p.Gly892Aspfs*17) identified in COL18A1 in a recessive form, a gene reported for Knobloch syndrome that manifests ID along with typical retinal abnormalities, and this phenotype was confirmed on reverse phenotyping. A mutation c.2134C>T (p.Arg712*) in TRAPPC9 has been found first time in the homozygous recessive form in our enrolled three affected siblings while it was previously reported in compound heterozygous form in a Caucasian descent. While fifth family remained unsolved. CONCLUSION: These mutations in four different genes with a recessive inheritance would be a contribution to the disease variant database of this devastating disorder.

Mutational spectrum of SMPD1 gene in Pakistani Niemann-Pick disease patients.

OBJECTIVE: Genetic variation analysis of rare autosomal recessive Niemann-Pick disease (NPD) Pakistani patients. METHODS: We sequenced the SMPD1 gene including its all coding and flanking regions in seven unrelated sporadic patients suffering from Niemann-Pick disease through targeted exome sequencing. Genetic variants mapping and their protein predictions were evaluated using different bioinformatics tools and clinical phenotypes were correlated. The study was conducted from January 2018 to March 2019 at The Children's Hospital Lahore. RESULTS: We have mapped five different mutations in SMPD1 gene of enrolled patients with a novel homozygous missense variant (c.1718G>C) (p.Trp573Ser) in one patient. A missense mutation (c.1267C>T) (p.His423Tyr) has been identified in three unrelated patients. A nonsense mutation (c.1327C>T) (p.Arg443Term) and one missense mutation (c.1493G>A) (p.Arg498His) mapped in one patient each. A compound heterozygous mutation has been mapped in one patient (c.740G>A) (p.Gly247Asp); (c.1493G>A) (p.Arg498His). Pathogenic effect of novel variant has been predicted through in-silico analysis and has not been reported in general overall population in the globe. CONCLUSION: This is the first report of genetic demographic assessment of Niemann-Pick disease in Pakistan. The mapped mutations would be helpful to build a disease variants algorithm of Pakistani population. This will be used for determining disease clinical magnitude along with provision of genetic screening services in affected families.