Identification of novel variants associated with Charcot Marie Tooth disease in a Pakistani
family
Sania Majeed1, Muhammad Irfan1, Zaib-un-Nisa1, Muhammad Shakeel1, Marium Zehra1,
Maleeha Zaman1, Ishtiaq Ahmad Khan1.
1 Jamil-ur-Rahman Center for Genome Research, Dr. Panjwani Center for Molecular Medicine
and Drug Research, International Center for Chemical and Biological Sciences, University of
Karachi, Karachi-75270, Pakistan
Abstract:
Charcot-Marie-Tooth (CMT) is a group of clinically and genetically heterogeneous disorders of
motor and sensory neuropathies, affecting 1 in 1500 to 1 in 10000 individuals. The disorder
primarily affects children, however, it can also affect adults up to the age of 30 or 40. The current
study aims to explore the genetic burden associated with CMT neuropathy in a Pakistani family.
The probands displayed a CMT2 phenotype, which includes symmetrical muscular atrophy and
slow-progressing weakness in the distal limbs. Nerve conduction study revealed compound muscle
action potential (CMAP) and sensory nerve action potential (SNAP) were absent in all right median,
ulnar, common, peroneal, and tibial nerves. The genetic burden of CMT patients in Pakistani family
was estimated by using targeted NGS of inherited genes by using MiSeq. Here, we identified three
novel non-synonymous variants predicted as pathogenic by SIFT, Mutation Taster, Provean, and
CADD Phred score (>15). One variant p.T245I located in the exon6 of GDAP1 was identified in
three patients in homozygous while was detected heterozygous in parents, while two variants i.e.,
EGR2 (p.T41P) and POLG (p.A791S) in the homozygous stages were identified in one patient.
Sanger-based sequencing analysis showed that the GDAP1 variant was noted homozygous in
probands, heterozygous in siblings and healthy parents while not found in healthy controls having
no family history of any neuropathy.