Modifier genes in microcephaly: A report on wdr62, cep63, rad50 and pcnt variants exacerbating disease caused by biallelic mutations of aspm and cenpj

Ehtisham Ul Haq Makhdoom, Syeda Seema Waseem, Maria Iqbal, Uzma Abdullah, Ghulam Hussain, Maria Asif, Birgit Budde, Wolfgang Höhne, Sigrid Tinschert, Saadia Maryam Saadi, Hammad Yousaf, Zafar Ali, Ambrin Fatima, Emrah Kaygusuz, Ayaz Khan, Muhammad Jameel, Sheraz Khan, Muhammad Tariq, Iram Anjum, Janine AltmüllerHolger Thiele, Stefan Höning, Shahid Mahmood Baig, Peter Nürnberg, Muhammad Sajid Hussain

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Congenital microcephaly is the clinical presentation of significantly reduced head circumfer-ence at birth. It manifests as both non-syndromic—microcephaly primary hereditary (MCPH)—and syndromic forms and shows considerable inter-and intrafamilial variability. It has been hypothesized that additional genetic variants may be responsible for this variability, but data are sparse. We have conducted deep phenotyping and genotyping of five Pakistani multiplex families with either MCPH (n = 3) or Seckel syndrome (n = 2). In addition to homozygous causal variants in ASPM or CENPJ, we discovered additional heterozygous modifier variants in WDR62, CEP63, RAD50 and PCNT—genes already known to be associated with neurological disorders. MCPH patients carrying an additional heterozygous modifier variant showed more severe phenotypic features. Likewise, the phenotype of Seckel syndrome caused by a novel CENPJ variant was aggravated to microcephalic osteodysplastic primordial dwarfism type II (MOPDII) in conjunction with an additional PCNT variant. We show that the CENPJ missense variant impairs splicing and decreases protein expression. We also observed centrosome amplification errors in patient cells, which were twofold higher in MOPDII as compared to Seckel cells. Taken together, these observations advocate for consideration of additional variants in related genes for their role in modifying the expressivity of the phenotype and need to be considered in genetic counseling and risk assessment.

Original languageEnglish
Article number731
JournalGenes
Volume12
Issue number5
DOIs
Publication statusPublished - May 2021

Keywords

  • Impaired splicing
  • MCPH
  • Modifier alleles
  • Primordial dwarfism
  • Seckel syndrome
  • Supernumerary centrosomes

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