Molecular characterization of recessively inherited ataxic and neuropathic disorders in consanguineous Pakistani families.

Autosomal recessive ataxia is characterized primarily by gait and balance problems. Peripheral neuropathy, which affects peripheral nervous system is manifested as sensory loss, pain, numbness and/or burning sensation accompanied by distal muscle atrophy which can cause limb deformities. We recruited seven consanguineous families having symptoms of peripheral neuropathy or ataxia for the identification of possible genetic defects underlying their disease conditions. Exome sequencing was completed for multiple participants of each family and data were filtered to retain rare deleterious variants. We identified disease-causing variants for five out of seven families. Different variants of GDAP1 were delineated in members of two families; while those of AFG3L2, MFSD8 and SETX affected members in one family each. Interestingly, one patient was homozygous for both a GDAP1 and a pathogenic MMACHC variant. Genetic heterogeneity was observed in one family since a homozygous frameshift variant of ALS2 was found in a patient while it was absent in his two affected first cousins. No genetic cause was identified for these two patients and those in another family. Hence, exome sequencing pinpointed molecular causes of recessively inherited ataxia or peripheral neuropathy in five participating families. This research has broadened the clinical spectrum of some of these genetic disorders.