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

Abstract

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.

• Authors: Iqra Ghulam Rasool, Muhammad Yasir Zahoor, Muhammad Iqbal, Aftab Ahmad Anjum, Fatima Ashraf, Hafiz Qamar Abbas, Hafiz Muhammad Azhar Baig, Tariq Mahmood, Wasim Shehzad
• Journal: Genes & genomics (Genes Genomics) Vol. 43 Issue 5 Pg. 503-512 (05 2021) ISSN: 2092-9293 [Electronic] Korea (South)
• PMID: 33710595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• COL18A1 protein, human
• Collagen Type XVIII
• GRM1 protein, human
• Intercellular Signaling Peptides and Proteins
• Proto-Oncogene Proteins
• Receptors, Metabotropic Glutamate
• TRAPPC9 protein, human
• Protein-Tyrosine Kinases
• ROS1 protein, human

Topics

• Adult
• Child
• Collagen Type XVIII (genetics)
• Consanguinity
• Female
• Humans
• Intellectual Disability (genetics, pathology)
• Intercellular Signaling Peptides and Proteins (genetics)
• Male
• Mutation
• Pedigree
• Phenotype
• Protein-Tyrosine Kinases (genetics)
• Proto-Oncogene Proteins (genetics)
• Receptors, Metabotropic Glutamate (genetics)
• Exome Sequencing