Ann Lab Med.  2021 May;41(3):350-353. 10.3343/alm.2021.41.3.350.

A Novel De Novo Heterozygous ARID1A Missense Variant Cluster in cis c.[5954C>G;6314C>T;6334C>T; 6843G>C] causes a Coffin–Siris Syndrome

• Lee CG
• Ki CS

• KMID: 2512698
• DOI: http://doi.org/10.3343/alm.2021.41.3.350

Figure

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  Fig. 1 Photograph and magnetic resonance imaging and electroencephalography results of the patient at six years of age. (A, B) She has distinctive, coarse facial features, including a low frontal hairline, broad eyebrows, long eyelashes, puffy eyelids, a depressed nasal bridge, anteverted nares, a wide mouth, a thick and everted lower lip, and low-set ears with dysmorphic pinnae. (C, D) She has short distal phalanges of the fifth fingers and fifth toes and clinodactyly of the fifth fingers. (E, F) T1-weighted axial and T2-weighted sagittal brain magnetic resonance images show a nearly 6.6-cm arachnoid cyst in the posterior fossa (indicated by red arrows) and a short splenium of the corpus callosum (indicated by a blue arrow). (G) The electroencephalography images show interictal epileptiform discharges during sleep on right posterior head lesions.

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  Fig. 2 Sanger sequencing and schematic view of the protein domain, all coding exons, and localization of all four novel ARID1A variants. (A) Sanger sequencing chromatograms of the four novel heterozygous variants c.[5954C>G;6314C>T;6334C>T;6843G>C] of ARID1A (NM_006015.6) in the patient and the wild-type genotype in her unaffected parents. (B) All four variants occurred in cis configuration. (C) ARID1A contains 20 exons and encodes the ARID1A protein, which contains 2,285 amino acids. (D) The ARID1A domain, according to UniProt (https://www.uniprot.org/uniprot/O14497) and Pfam (http://pfam.xfam.org/protein/O14497) databases showing previously reported ARID1A variants in CSS patients (upper panel) base on the HGMD Professional database (http://www.hgmd.cf.ac.uk/ac/all.php)and the four co-occurring variants identified in our patient (lower panel). To date, 18 heterozygous truncating ARID1A variants have been reported, including nine nonsense, six frameshift, and three splicing variants. Two missense variants have been indicated to be possibly associated with CSS. Purple bar indicates frameshift variant; blue bar indicates nonsense variant; green bar indicates splice-site variant; red bar indicates missense variant. Abbreviations: ARID, AT-rich interaction domain; BAF250_C domain, C-terminal folded region; CSS, Coffin–Siris syndrome.

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