Genetic analysis in three inherited disorders

Abstract

Genes responsible for inherited disorders can be localized on the genome by genetic linkage analysis. Mapping of a disease locus is accomplished by genotyping the family members with polymorphic markers in order to identify crossovers and observe allele segregation with the disease. Initially, a whole-genome scan is conducted to identify genotypes. Possible loci are determined using linkage programs and then further investigated by fine-mapping using densely spaced markers. After finding the disease locus, candidate gene approach is applied to identify the causative defect and thus the gene responsible for the disease. In this study genetic investigation was performed on three hereditary diseases. Focal dermal hypoplasia (FDH) commonly manifests with dermal, skeletal, ocular, oral and soft tissue abnormalities. X-linked inheritance of the disorder allowed omitting the genome scan in favor of a dense mapping of the X chromosome. The locus found was narrowed down by fine mapping. The number of genes residing at the identified gene locus was too large to allow a simple search for the disease gene. At that time, a gene at the locus, PORCN, was reported to be the disease gene, so it was screened for mutations in the family studied. No mutation was found; however, gene expression in patients was found reduced. Autosomal recessive microhydranencephaly (MHAC) is congenital and refers to the rare co-occurrence of microcephaly and hydranencephaly, with gene locus at chromosome 16p13.13-p12.2. We applied candidate gene approach and analyzed three genes at the locus and found a deletion (c.1-3548_83+644del) in NDE1. Frequent occurrence of brain tumors was observed in a non-consanguineous family, indicating familial inheritance. Genetic linkage analysis performed related the condition to a locus; however, the results were inconclusive as the penetrance value of the condition was unascertainable.