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Background <p>The diagnosis of neurogenetic disorders is often prolonged due to clinical variability and significant genetic heterogeneity, making molecular diagnosis challenging. This study aimed to investigate the molecular basis of rare inherited neurological conditions in three consanguineous Moroccan families.</p> Methods <p>We performed Whole exome sequencing (WES) on probands from three unrelated consanguineous Moroccan families (NP 69, NP 84, NP 89). Candidate variants were validated by Sanger sequencing and segregated within the families. Pathogenicity was assessed through in silico prediction tools. Molecular modeling and molecular dynamics simulations were applied to assess the structural impact of selected variants.</p> Results <p>Whole exome sequencing revealed likely disease-causing variants in all three families. In Family NP 69, we found compound heterozygous missense variants in <i>RYR3</i> gene (p.Gly2168Arg and p.Val854Ile) in a proband presenting with developmental delay and hippocampal sclerosis. In Family NP 84, a homozygous missense variant (p.Trp671Arg) in <i>POLR3A</i> gene, was associated with classic hypomyelinating leukodystrophy and ataxia, but with atypical features including preserved cognition, myoclonus, and oligodontia, consistent with recurrence of a previously reported variant in North Africa and suggestive of a possible founder effect. In Family NP 89, a homozygous splice-site mutation in <i>LAMA2</i> gene (c.8244 + 1G &gt; A) was confirmed in a proband with severe congenital muscular dystrophy.</p> Conclusion <p>This study reports a novel compound heterozygous configuration in <i>RYR3</i>, confirms a previously reported bi-allelic variant in <i>POLR3A</i>, and validates a recurrent <i>LAMA2</i> variant. Together, these findings add new insights into the genotype–phenotype spectrum of neurogenetic disorders in consanguineous North African populations, all consistent with a shared autosomal recessive inheritance pattern.</p>

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Expanding the genetic spectrum of neurogenetic disorders in moroccan families by exome sequencing: identification of candidate variants in RYR3, POLR3A, and LAMA2

  • 期刊论文

  • 发表日期：

    2026年5月11日

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  • Fatima Ezzahra Chentoufi,
  • Assia Idyahia,
  • Madoussou Toure,
  • Adil El Hamouchi,
  • Abdelhamid Barakat,
  • Houda Benrahma,
  • Hicham Charoute

摘要

Background

The diagnosis of neurogenetic disorders is often prolonged due to clinical variability and significant genetic heterogeneity, making molecular diagnosis challenging. This study aimed to investigate the molecular basis of rare inherited neurological conditions in three consanguineous Moroccan families.

Methods

We performed Whole exome sequencing (WES) on probands from three unrelated consanguineous Moroccan families (NP 69, NP 84, NP 89). Candidate variants were validated by Sanger sequencing and segregated within the families. Pathogenicity was assessed through in silico prediction tools. Molecular modeling and molecular dynamics simulations were applied to assess the structural impact of selected variants.

Results

Whole exome sequencing revealed likely disease-causing variants in all three families. In Family NP 69, we found compound heterozygous missense variants in RYR3 gene (p.Gly2168Arg and p.Val854Ile) in a proband presenting with developmental delay and hippocampal sclerosis. In Family NP 84, a homozygous missense variant (p.Trp671Arg) in POLR3A gene, was associated with classic hypomyelinating leukodystrophy and ataxia, but with atypical features including preserved cognition, myoclonus, and oligodontia, consistent with recurrence of a previously reported variant in North Africa and suggestive of a possible founder effect. In Family NP 89, a homozygous splice-site mutation in LAMA2 gene (c.8244 + 1G > A) was confirmed in a proband with severe congenital muscular dystrophy.

Conclusion

This study reports a novel compound heterozygous configuration in RYR3, confirms a previously reported bi-allelic variant in POLR3A, and validates a recurrent LAMA2 variant. Together, these findings add new insights into the genotype–phenotype spectrum of neurogenetic disorders in consanguineous North African populations, all consistent with a shared autosomal recessive inheritance pattern.