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Background <p>Microcephaly primary hereditary (MCPH) is characterized by a reduced occipitofrontal circumference. We assessed the clinical and genetic characteristics of three Iranian individuals from two consanguineous families diagnosed with MCPH.</p> Methods and results <p>Probands underwent whole-exome sequencing (WES). Sanger sequencing was used to confirm the candidate mutation and to analyze segregation within family members. Various in silico tools were employed to evaluate the impact of the identified variant on the structure and function of the associated protein. Additionally, RT-PCR was conducted to examine how the identified variant affected the size of the mRNA. A novel homozygous variant, NM_001083961.1: c.2115&#xa0;C &gt; T: p.(Gly705=), located in exon 17 of <i>WDR62</i> gene, known to be a causative factor for MCPH2, was discovered in all three individuals with primary microcephaly. Notably, some phenotypic variability and new clinical features were observed among our patients. Although this variant is synonymous, it creates a new donor splicing site in exon 17 that connects with the acceptor splicing site of the adjacent intron 17, leading to the deletion of 33 nucleotides from exon 17. Although this deletion does not alter the reading frame, it removes 11 essential amino acids necessary for the normal functioning of WDR62. Gel electrophoresis and sequencing of RT-PCR products confirmed the presence of this 33-nucleotide deletion.</p> Conclusions <p>Our findings broaden the range of identified mutations in the <i>WDR62</i> gene and expand the clinical spectrum of MCPH2, highlighting the effectiveness and cost-efficiency of WES for molecular diagnosis in genetically diverse disorders such as MCPH.</p>

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Whole-exome sequencing reveals a novel variant in two Iranian families with autosomal recessive primary microcephaly

  • 期刊论文

  • 发表日期：

    2025年7月22日

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  • Mahta Mazaheri,
  • Zahra Sadr,
  • Naeim Ehtesham,
  • Mahdieh Yavari,
  • Hossein Ahrar,
  • Hossein Khodaei

摘要

Background

Microcephaly primary hereditary (MCPH) is characterized by a reduced occipitofrontal circumference. We assessed the clinical and genetic characteristics of three Iranian individuals from two consanguineous families diagnosed with MCPH.

Methods and results

Probands underwent whole-exome sequencing (WES). Sanger sequencing was used to confirm the candidate mutation and to analyze segregation within family members. Various in silico tools were employed to evaluate the impact of the identified variant on the structure and function of the associated protein. Additionally, RT-PCR was conducted to examine how the identified variant affected the size of the mRNA. A novel homozygous variant, NM_001083961.1: c.2115 C > T: p.(Gly705=), located in exon 17 of WDR62 gene, known to be a causative factor for MCPH2, was discovered in all three individuals with primary microcephaly. Notably, some phenotypic variability and new clinical features were observed among our patients. Although this variant is synonymous, it creates a new donor splicing site in exon 17 that connects with the acceptor splicing site of the adjacent intron 17, leading to the deletion of 33 nucleotides from exon 17. Although this deletion does not alter the reading frame, it removes 11 essential amino acids necessary for the normal functioning of WDR62. Gel electrophoresis and sequencing of RT-PCR products confirmed the presence of this 33-nucleotide deletion.

Conclusions

Our findings broaden the range of identified mutations in the WDR62 gene and expand the clinical spectrum of MCPH2, highlighting the effectiveness and cost-efficiency of WES for molecular diagnosis in genetically diverse disorders such as MCPH.