Novel Variants in MPV17, PRX, GJB1, and SACS Cause Charcot–Marie–Tooth and Spastic Ataxia of Charlevoix–Saguenay Type Diseases

Abstract

Charcot–Marie–Tooth disease (CMT) and autosomal recessive spastic ataxia of Charlevoix–Saguenay type (ARSACS) are large heterogeneous groups of sensory, neurological genetic disorders characterized by sensory neuropathies, muscular atrophies, abnormal sensory conduction velocities, and ataxia. CMT2EE (OMIM: 618400) is caused by mutations in MPV17 (OMIM: 137960), CMT4F (OMIM:614895) is caused by PRX (OMIM: 605725), CMTX1 (OMIM:302800) is caused by mutations in GJB1 (OMIM: 304040), and ARSACS (OMIM:270550) is caused by mutations in SACS (OMIM: 604490). In this study, we enrolled four families: DG-01, BD-06, MR-01, and ICP-RD11, with 16 affected individuals, for clinical and molecular diagnoses. One patient from each family was analyzed for whole exome sequencing and Sanger sequencing was done for the rest of the family members. Affected individuals of families BD-06 and MR-01 show complete CMT phenotypes and family ICP-RD11 shows ARSACS type. Family DG-01 shows complete phenotypes for both CMT and ARSACS types. The affected individuals have walking difficulties, ataxia, distal limb weakness, axonal sensorimotor neuropathies, delayed motor development, pes cavus, and speech articulations with minor variations. The WES analysis in an indexed patient of family DG-01 identified two novel variants: c.83G>T (p.Gly28Val) in MPV17 and c.4934G>C (p.Arg1645Pro) in SACS. In family ICP-RD11, a recurrent mutation that causes ARSACS, c.262C>T (p.Arg88Ter) in SACS, was identified. Another novel variant, c.231C>A (p.Arg77Ter) in PRX, which causes CMT4F, was identified in family BD-06. In family MR-01, a hemizygous missense variant c. 61G>C (p.Gly21Arg) in GJB1 was identified in the indexed patient. To the best of our knowledge, there are very few reports on MPV17, SACS, PRX, and GJB1 causing CMT and ARSACS phenotypes in the Pakistani population. Our study cohort suggests that whole exome sequencing can be a useful tool in diagnosing complex multigenic and phenotypically overlapping genetic disorders such as Charcot–Marie–Tooth disease (CMT) and spastic ataxia of Charlevoix–Saguenay type.

Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families

“…In societies such as Pakistan, where consanguineous marriages are common, the incidence of mutant alleles is higher. 22,38 To mitigate this, premarital testing, newborn genetic disorder screening and parental genetic screening can be undertaken to reduce the disease allele burden. Carrier genetic screening, parental counseling and neonatal work-up are also recommended for future progeny.…”

“…Carrier genetic screening, parental counseling and neonatal work-up are also recommended for future progeny. 22,[38][39][40] Whole exome sequencing can be used as the primary molecular diagnostic tool in cutis laxa patients. 41,42 This approach is highly efficient and more precise in large consanguineous families.…”

“…41,42 This approach is highly efficient and more precise in large consanguineous families. 22,38 Therefore, reporting further cases associated with this gene could aid…”

“…The variations reported here in this study have not been identified before in the Pakistani population. In societies such as Pakistan, where consanguineous marriages are common, the incidence of mutant alleles is higher 22,38 . To mitigate this, premarital testing, newborn genetic disorder screening and parental genetic screening can be undertaken to reduce the disease allele burden.…”

“…To mitigate this, premarital testing, newborn genetic disorder screening and parental genetic screening can be undertaken to reduce the disease allele burden. Carrier genetic screening, parental counseling and neonatal work‐up are also recommended for future progeny 22,38–40 . Whole exome sequencing can be used as the primary molecular diagnostic tool in cutis laxa patients 41,42 .…”