Molecular genetics, neuroimaging outcomes, and structural analyses of novel and recurrent variants of WDR62 gene in two consanguineous Pakistani families with autosomal recessive primary microcephaly

Komal Aslam, Aysha Saeed, Hafiza Iqra Saeed, Rasheeda Bashir, Hanna Abid, Roeha Akhtar, Nida Habib, Ramisha Khan, Roha Asif, Shereen Rafiq, Maria Asif, Ehtisham Ul Haq Makhdoom, Muhammad Sajid Hussain, Shahid Mahmood Baig, Iram Anjum

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental and genetically heterogeneous disorder, characterized by small cranium size (> - 3 SD below mean) and often results in varying degree of intellectual disability. Thirty genes have been identified for the etiology of this disorder due to its clinical and genetic heterogeneity. METHODS AND RESULTS: Here, we report two consanguineous Pakistani families affected with MCPH exhibiting mutation in WDR62 gene. The investigation approach involved Next Generation Sequencing (NGS) gene panel sequencing coupled with linkage analysis followed by validation of identified variants through automated Sanger sequencing and Barcode-Tagged (BT) sequencing. The molecular genetic analysis revealed one novel splice site variant (NM_001083961.2(WDR62):c.1372-1del) in Family A and one known exonic variant NM_001083961.2(WDR62):c.3936dup (p.Val1313Argfs*18) in Family B. Magnetic Resonance Imaging (MRI) scans were also employed to gain insights into the structural architecture of affected individuals. Neurological assessments showed the reduced gyral and sulcal patterns along with normal corpus callosum in affected individuals harboring novel variant. In silico assessments of the identified variants were conducted using different tools to confirm the pathogenicity of these variants. Through In silico analyses, both variants were identified as disease causing and protein modeling of exonic variant indicates subtle conformational alterations in prophesied protein structure. CONCLUSION: This study identifies a novel variant (c.1372-1del) and a recurrent pathogenic variant c.3936dup (p.Val1313Argfs*18) in the WDR62 gene among the Pakistani population, expanding the mutation spectrum for MCPH. These findings emphasize the importance of genetic counseling and awareness to reduce consanguinity and address the burden of this disorder.

Original languageEnglish
Pages (from-to)783
Number of pages1
JournalMolecular Biology Reports
Volume51
Issue number1
DOIs
Publication statusPublished - 26 Jun 2024
Externally publishedYes

Keywords

  • WDR62 gene
  • In silico analysis
  • Next generation sequencing
  • Novel mutation
  • Primary microcephaly
  • Protein modeling

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