Mosaicism in rare disease

Avigdor, Bracha Erlanger; Osei-Owusu, Ikeoluwa A.; Pevsner, Jonathan

doi:10.1016/b978-0-12-820140-4.00003-x

Cited by 1 publication

(1 citation statement)

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“…Finding of the same “de novo” variant in both the siblings, suggesting a parent germline mosaicism in this case. Germline mosaicism is a relatively frequent mechanism of inherited disease and provides an explanation for the inheritance pattern in cases where multiple affected offspring are born to healthy parents, and recent next‐generation sequencing methods have improved the sensitivity to detect mosaic events (Avigdor et al, 2021 ). However, we could not find out if KIF2A variant G440R was paternal or maternal, and, thus, an early prenatal diagnosis would be necessary for further pregnancy in this family.…”

Section: Discussionmentioning

confidence: 99%

Mutations obstructing ATP's emplacement in KIF2A nucleotide‐binding pocket causes parenchymal malformations, motor developmental delay, with intellectual disability

Zhao

Chen

et al. 2023

Molec Gen & Gen Med

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BackgroundKIF2A‐related tubulinopathy (MIM: #615411) is a very rare disorder that was clinically characterized as microcephaly, epilepsy, motor developmental disorder (MDD), and various malformations of cortical development, but intellectual disability (ID) or global developmental delay (GDD) was rarely reported in the patients.MethodsQuad whole‐exome sequencing (WES) was performed on the proband, the older brother, and their parents. Sanger sequencing was used to verify the candidate gene variant.ResultsThe proband, a 23‐month‐old boy, was previously diagnosed with GDD, and his brother, aged nine years, had ID; both were born to a healthy couple. Quad‐WES detected a novel heterozygous KIF2A variant, c.1318G>A (p.G440R), in both the brothers but not in the parents. In‐silico analysis revealed that the variants G440R and G318R (which were previously reported in the only reported patient with GDD) lead to markedly enlarged side chains and hinder ATP's emplacement in the NBD pocket.ConclusionsThe type of KIF2A variants that sterically hinder ATP emplacing in KIF2A NBD pocket may be associated with the intellectual disability phenotype; however, further studies are needed. Findings in this case also suggest a rare parental germline mosaicism of KIF2A G440R.

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Section: Discussionmentioning

confidence: 99%