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Founder effect and endogamy result in the high prevalence of Junctional Herlitz Epidermolysis Bullosa in a community from Southern India

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction:
The evolutionary studies suggest that many communities in India have a high risk of developing population-specific autosomal recessive genetic disorders due to founder events and endogamy. The next step would be to identify specific recessive diseases among various subpopulations and elucidate the underlying genes/variants responsible for them. Here we present an endogamous community (with a strong founder effect) from Southern India that has significantly higher incidents of Junctional Herlitz Epidermolysis Bullosa (JHEB), a rare genetic skin disorder, than the expected frequencies worldwide. The study aims to identify and functionally characterize the genetic variants causing JHEB in the community to develop predictive diagnostic indicators for this high-priority genetic disorder prevalent within this population in a community-specific manner.

Methods:
Exome and targeted re-sequencing methods were used to identify novel and ultra-rare genetic variants in LAMC2 and LAMB3 genes as causes of JHEB in endogamous communities from Southern India. The patient-specific LAMB3 variant was introduced in the mouse genome using CRISPR-Cas9-based genome editing technology. Genetically modified homozygous mice were used to functionally characterize the disease.

Results:
We identified novel and ultra-rare genetic variants in LAMC2 and LAMB3 genes, respectively, as causes of JHEB in two unrelated families from different endogamous communities from Southern India. The children carrying these variants in homozygous conditions develop severe symptoms of JHEB one week after their birth, subsequently die within two months of their age.

Later, we identified a total of 12 unrelated families, with a history of the disease. As we predicted, the parents were found heterozygous carriers in each family with the same identified LAMB3 variant. All these families belong to one community and follow endogamous marriage.

The identified LAMB3 variant is found only in two individuals (in heterozygous condition) out of 8,62,115 individuals (frequency 1.15*10-6) from the overall world population's genetic database. We screened 13,872 samples representing the whole Indian population and the variant is not found in other Indian communities. The mitochondrial haplogroup analysis of the individuals from the community suggests that 67% of them belong to the R30b2 haplogroup and the community is highly endogamous. Chromosomal phasing and haplotype analysis suggest that the heterozygous carriers from the 12 unrelated families carry at least 2.64 Mb identical genomic segments (surrounding the identified LAMB3 variant), present in the homozygous condition in the affected child.

The mouse model with patient-specific LAMB3 variant showed neonatal deaths (within 48 hours after birth) in homozygous conditions, replicating the infant mortality observed among affected children. The pups also develop the JHEB phenotypes confirming that the identified mutation is the cause of the disease in the affected children. The internal organs including the heart, spleen, and uterus were significantly enlarged due to inflammation.

Conclusion:
Our study, for the first time, identified and functionally validated an ultra-rare pathogenic LAMB3 variant (previously classified as a “Variant of Uncertain Significance” according to ACMG classification) as the cause of JHEB in many families belonging to a community (with strong founder effect and endogamy) from Southern India. As a public health intervention, we have applied for permission from the State's "Directorate of Public Health and Preventive Medicine” to conduct genetic screening of the entire community which consists of about 5,000 people. This would help us in estimating the overall disease burden accurately and also in identifying and providing appropriate counselling to the heterozygous carriers at the reproductive age and children so that the disease can be avoided in the future generation. The prenatal genetic screening of growing fetuses from heterozygous pregnant mothers will help in identifying the embryos carrying the homozygous mutation so that appropriate counselling can be provided to the parents to avoid the birth of affected babies.

 

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