Background
Hereditary motor and sensory neuropathy (HMSN) refers to a group of inherited progressive peripheral neuropathies characterized by reduced nerve conduction velocity with chronic segmental demyelination and/or axonal degeneration. HMSN is highly clinically and genetically heterogeneous with multiple inheritance patterns and phenotypic overlap with other inherited neuropathies and neurodegenerative diseases. Due to this high complexity and genetic heterogeneity, this study aimed to elucidate the genetic causes of HMSN in Pakistani families using Whole Exome Sequencing (WES) for variant identification and Sanger sequencing for validation and segregation analysis, facilitating accurate clinical diagnosis.
Methods
Families from Khyber Pakhtunkhwa with at least two members showing HMSN symptoms, who had not previously undergone genetic analysis, were included. Referrals for genetic investigations were based on clinical features suggestive of HMSN by local neurologists. WES was performed on affected individuals from each family, with Sanger sequencing used to validate and analyze the segregation of identified variants among family members. Clinical data including age of onset were assessed for variability among affected individuals, and the success rate of genetic diagnosis was compared with existing literature using proportional differences and Cohen’s h.
Results
WES identified homozygous pathogenic variants in
GDAP1
(c.310 + 4 A > G, p.?),
SETX
(c.5948_5949del, p.(Asn1984Profs*30),
IGHMBP2
(c.1591 C > A, p.(Pro531Thr) and
NARS1
(c.1633 C > T, p.(Arg545Cys) as causative for HMSN in five out of nine families, consistent with an autosomal recessive inheritance pattern. Additionally, in families with HMSN, a
SETX
variant was found to cause cerebellar ataxia, while a
NARS1
variant was linked to intellectual disability. Based on American College of Medical Genetics and Genomics criteria, the
GDAP1
variant is classified as a variant of uncertain significance, while variants in
SETX
and
IGHMBP2
are classified as pathogenic, and the
NARS1
variant is classified as likely pathogenic. The age of onset ranged from 1 to 15 years (Mean = 5.13, SD = 3.61), and a genetic diagnosis was achieved in 55.56% of families with HMSN, with small effect sizes compared to previous studies.
Conclusions
This study expands the molecular genetic spectrum of HMSN and HMSN plus type neuropathies in Pakistan and facilitates accurate diagnosis, genetic counseling, and clinical management for affected families.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12883-024-03882-y.
