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Primary microcephaly, primordial dwarfism, and brachydactyly in adult cases with biallelic skipping of RTTN exon 42
Author(s) -
Zakaria Muhammad,
Fatima Ambrin,
Klar Joakim,
Wikström Johan,
Abdullah Uzma,
Ali Zafar,
Akram Talia,
Tariq Muhammad,
Ahmad Habib,
Schuster Jens,
Baig Shahid M,
Dahl Niklas
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23755
Subject(s) - brachydactyly , biology , microcephaly , genetics , exon , frameshift mutation , dwarfism , phenotype , allele , gene , endocrinology , short stature
Biallelic and pathogenic variants in the RTTN gene, encoding the centrosomal protein Rotatin, are associated with variable degrees of neurodevelopmental abnormalities, microcephaly, and extracranial malformations. To date, no reported case has reached their third decade. Herein, we report on a consanguineous family with three adult members, age 43, 57, and 60 years respectively, with primary microcephaly, developmental delay, primordial dwarfism, and brachydactyly segregating a homozygous splice site variant NM_173630.3:c.5648–5T>A in RTTN . The variant RTTN allele results in a nonhypomorphic skipping of exon 42 and a frameshift [(NP_775901.3:p.Ala1883Glyfs*6)]. Brain MRI of one affected individual showed markedly reduced volume of cerebral lobes and enlarged sulci but without signs of neural migration defects. Our assessment of three adult cases with a biallelic RTTN variant shows that a predicted shortened Rotatin, lacking the C‐terminal end, are associated with stationary clinical features into the seventh decade. Furthermore, our report adds brachydactyly to the phenotypic spectrum in this pleiotropic entity.