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- Title
A novel nonsense variant in ARID1B causing simultaneous RNA decay and exon skipping is associated with Coffin-Siris syndrome.
- Authors
Sofronova, Viktoriia; Fukushima, Yu; Masuno, Mitsuo; Naka, Mami; Nagata, Miho; Ishihara, Yasuki; Miyashita, Yohei; Asano, Yoshihiro; Moriwaki, Takahito; Iwata, Rina; Terawaki, Seigo; Yamanouchi, Yasuko; Otomo, Takanobu
- Abstract
Coffin-Siris syndrome (CSS) is a congenital disorder that is characterized by an absent/hypoplastic fifth distal phalanx, psychomotor developmental delay, and coarse facial features. One of the causative genes, ARID1B (AT-rich interactive domain-containing protein 1B), encodes components of the BAF chromatin remodeling complexes. Here, we report a case of a 3-year 8-month-old male with a novel nonsense variant (NM_001374820.1:c.4282C > T, p.(Gln1428*)) in the ARID1B gene, which was identified with whole-exome sequencing. He showed clinical symptoms of cleft soft palate, distinctive facial features (flat nasal bridge, thick eyebrows, and long eyelashes), right cryptorchidism, and hypertrichosis that partially overlapped with CSS. One of the most characteristic features of CSS is absent/hypoplastic fifth distal phalanx. He showed no obvious clinical finding in the lengths of his fingers or in the formation of his fingernails. However, radiographic analyses of the metacarpophalangeal bones revealed shortening of all the distal phalanges and fifth middle phalanges, suggesting brachydactyly. We performed mRNA analyses and revealed that both nonsense-mediated decay and nonsense-associated altered splicing were simultaneously caused by the c.4282C > T nonsense variant. The proband's clinical manifestations fit the previously reported criteria of disease for CSS or intellectual disability with ARID1B variant. Altogether, we suggest that c.4282C > T is a pathogenic variant that causes this clinical phenotype. Coffin-Siris syndrome: New mutation implicated Genomic sequencing has revealed a new causative mutation for Coffin-Siris syndrome (CSS), a very rare disease characterized by developmental delays, intellectual disability and various anatomical abnormalities. A team from Japan led by Takanobu Otomo of Kawasaki Medical School in Kurashiki performed genetic sequencing on a young boy who showed many hallmark features of CSS. The researchers identified a previously undescribed mutation in ARID1B, a gene previously linked to the disease. The mutation introduced a premature stop signal into the ARID1B gene transcript. The boy's cells responded to the genetic defect by activating two kinds of RNA surveillance mechanisms: one that helped eliminate the faulty transcript, and another designed to alter splicing patterns. The findings could help the medical community diagnosis other cases of CSS and ultimately find treatments.
- Subjects
PAPHOS (Cyprus); CONGENITAL disorders; CHROMATIN-remodeling complexes; DIAGNOSIS; SYMPTOMS; RNA; DEVELOPMENTAL delay; EYELASHES
- Publication
Human Genome Variation, 2022, Vol 9, Issue 1, p1
- ISSN
2054-345X
- Publication type
Article
- DOI
10.1038/s41439-022-00203-y