A novel leaky splice variant in centromere protein J (CENPJ)-associated Seckel syndrome

Navneesh Yadav, Laxmi Kirola, Thenral S. Geetha, Kirti Mittal, Jayarama Kadandale, Yuval Yogev, Ohad S. Birk, Neerja Gupta, Prahlad Balakrishnan, Manisha Jana, Meena Gupta, Madhulika Kabra, Bittianda Kuttapa Thelma

Research output: Contribution to journalArticlepeer-review


Abstract: Primary microcephaly and Seckel syndrome are rare genetically and clinically heterogenous brain development disorders. Several exonic/splicing mutations are reported for these disorders to date, but ∼40% of all cases remain unexplained. We aimed to uncover the genetic correlate(s) in a family of multiple siblings with microcephaly. A novel homozygous intronic variant (NC_000013.10:g.25459823T>C) in CENPJ (13q12) segregating with all four affected male siblings was identified by exome sequencing and validated by targeted linkage approach (logarithm of the odds score 1.8 at θ 0.0). RT-PCR of CENPJ in affected siblings using their EBV derived cell lines showed aberrant transcripts suggestive of exon skipping confirmed by Sanger sequencing. Significantly reduced wild type transcript/protein in the affected siblings having the splice variant indicates a leaky gene expression of pathological relevance. Based on known CENPJ function, assessing for mitotic alterations revealed defect in centrosome duplication causing mono/multicentrosome(s) at prophase, delayed metaphase, and unequal chromosomal segregation in patient cells. Clinical features witnessed in this study expand the spectrum of CENPJ-associated primary microcephaly and Seckel syndrome. Furthermore, besides the importance of regulatory variants in classical monogenic disorders these findings provide new insights into splice site biology with possible implications for ASO-based therapies.

Original languageEnglish
Pages (from-to)245-256
Number of pages12
JournalAnnals of Human Genetics
Issue number5
StatePublished - 1 Sep 2022


  • SRp40
  • Seckel syndrome
  • alternate splicing
  • cell division defects
  • primary microcephaly

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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