Homozygosity stretches around homozygous mutations in autosomal recessive disorders: patients from nonconsanguineous Indian families

Abstract

India has a large heterogeneous population with its unique social and genetic characteristics. Tradition of marriage between specific caste groups have produced unique characteristics to the mutation spectrum of genetic disorders and may be a higher prevalence of autosomal recessive (AR) disorders in some communities. We observed that in many nonconsanguineous families with rare autosomal disorders, maternally and paternally inherited mutations are same, indicating common ancestor. In this era of genomic techniques, finding homozygous regions have become easy. It was seen that the patients with AR disorders, who were homozygous for the disease causing pathogenic / likely pathogenic variations, have large stretches (0.6-188 Mb) of homozygosity around the causative sequence variations. SNP microarray data of patients from consanguineous and nonconsanguineous families also showed that even patients from nonconsanguineous families had 3-49 Mb size regions of homozygosity. Long stretches of homozygosity around homozygous rare pathogenic variants in nonconsanguineous families with rare AR disorders supports the notion that these couples may have a common ancestor for more than six generations and the system of marriages between same groups. Hence, using the strategy of homozygosity by descent even in nonconsanguineous families can be fruitful in identifying the novel pathogenic variations and novel genes.