Language
English
Publication Date
12-21-2024
DOI
10.3390/genes15121646
PMID
39766915
PMCID
PMC11728111
PubMedCentral® Posted Date
12-21-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Background: Leber congenital amaurosis (LCA) is a congenital onset severe form of inherited retinal dystrophy (IRD) and a common cause of pediatric blindness. Disease-causing variants in at least 14 genes are reported to predispose LCA phenotype. LCA is inherited as an autosomal recessive disease. It can be an isolated eye disorder or as part of a syndrome, such as Senior Loken or Joubert syndrome. Sequencing studies from consanguineous populations have proven useful for novel variants identification; thus, the present study aimed to explore the genetic heterogeneity of 15 consanguineous Pakistani families, each segregating a severe IRD phenotype using targeted next generation sequencing.
Methods: This study enrolled 15 consanguineous families, each with multiple affected cases of retinal dystrophy phenotype. DNA was extracted from blood samples. Targeted panel sequencing of 344 known genes for IRDs was performed, followed by Sanger sequencing for segregation analysis.
Results: Data analysis revealed a total of eight reported (c.316C>T and c.506G>A in RDH12; c.864dup and c.1012C>T in SPATA7, as well as c.1459T>C, c.1062_1068del, c.1495+1G>A, c.998G>A in the CRB1, LCA5, TULP1, and IFT140 genes, respectively) and four novel homozygous (c.720+1G>T in LCA5, c.196G>C in LRAT, c.620_625del in PRPH2, and c.3411_3414del in CRB1) variants segregating with disease phenotype in each respective family. Furthermore, a novel heterozygous variant of CRB1 gene, i.e., c.1935delC in compound heterozygous condition was found segregating with disease phenotype in one large family with multiple consanguinity loops.
Conclusion: Comprehensive molecular diagnosis of 15 consanguineous Pakistani families led to the identification of a total of 5 novel variants contributing to genetic heterogeneity of LCA-associated genes and helped to provide genetic counseling to the affected families.
Keywords
Humans, Leber Congenital Amaurosis, Male, Female, Consanguinity, Pakistan, Pedigree, Genetic Heterogeneity, Phenotype, Child, Mutation, High-Throughput Nucleotide Sequencing, Eye Proteins, Child, Preschool, Membrane Proteins, Adolescent, Alcohol Oxidoreductases, DNA-Binding Proteins, Leber congenital amaurosis, childhood blindness, autosomal recessive, genetic heterogeneity
Published Open-Access
yes
Recommended Citation
Akhtar, Zainab; Altaf, Sumaira; Li, Yumei; et al., "Phenotypic and Genetic Heterogeneity of a Pakistani Cohort of 15 Consanguineous Families Segregating Variants in Leber Congenital Amaurosis-Associated Genes" (2024). Faculty and Staff Publications. 4353.
https://digitalcommons.library.tmc.edu/baylor_docs/4353