Letter to the Editor
Ann Lab Med 2021; 41(3): 350-353
Published online May 1, 2021 https://doi.org/10.3343/alm.2021.41.3.350
Copyright © Korean Society for Laboratory Medicine.
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
1Department of Pediatrics, Nowon Eulji Medical Center, Eulji University, Seoul, Korea; 2GC Genome, Yongin, Korea
Correspondence to: Cha Gon Lee, M.D., Ph.D.
Division of Child Neurology, Department of Pediatrics, Nowon Eulji Medical Center, Eulji University, 68 Hangeulbiseok-ro, Nowon-gu, Seoul 01830, Korea
Tel: +82-2-970-8222, Fax: +82-2-970-0068, Email: firstname.lastname@example.org
Coffin–Siris syndrome (CSS; OMIM 135900) is a rare, clinically and genetically heterogeneous disorder . Several genes encoding components of the BRG1/BRM-associated factor (BAF) chromatin remodeling complex are involved in CSS development . AT-rich interaction domain 1A (ARID1A) is one of the largest core subunits of the BAF complex. ARID1A harbors an N-terminal DNA-binding ARID domain and a C-terminal folded region, recently annotated as the BAF250_C domain. Of the cases of molecularly-confirmed CSS reported worldwide, 5–7% have been attributed to pathogenic variants in
A six-year-old girl visited our clinic at Nowon Eulji Medical Center in August 2019, with a first generalized tonic seizure provoked by fever. She was the second child of non-consanguineous parents of Korean descent. She was born prematurely at 35 weeks and five days of gestation via vaginal delivery, with a low birth weight of 1,750 g (<3rd centile). Initial evaluation for multiple congenital abnormalities revealed a large perimembranous ventricular septal defect (VSD), patent foramen ovale (PFO), infantile hypertrophic pyloric stenosis (IHPS), left bifid ureter, double inferior vena cava, and uterine didelphys. She underwent pyloromyotomy for IHPS at the age of one month and VSD Dacron patch closure and PFO direct closure at the age of two months. She underwent surgical correction for bilateral congenital esotropia at 17 months and surgical removal of a left congenital cholesteatoma at 57 months. She has been receiving low-dose thyroid hormone (levothyroxine 25 μg/day) for subclinical hypothyroidism since four years of age.
From early infancy, she showed recognizable psychomotor developmental delay (DD) with hypotonia and hypermobile joints. She exhibited apparent language DDs, with receptive language being less affected than expressive language. She showed moderate intellectual disability (full-scale intelligence quotient, ~40) . Physical examination at six yrs of age revealed normal growth (Fig. 1).
Figure 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.
For whole-exome sequencing, SureSelect Human All Exon V5 (Agilent Technologies, Santa Clara, CA, USA) was used for library preparation, and sequencing was performed on the NextSeq500 platform (Illumina Inc., San Diego, CA, USA) at GC Genome (Yongin, Korea). A cluster of
Figure 2. Sanger sequencing and schematic view of the protein domain, all coding exons, and localization of all four novel
ARID1Avariants. (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) ARID1Acontains 20 exons and encodes the ARID1A protein, which contains 2,285 amino acids. (D) The ARID1Adomain, according to UniProt (https://www.uniprot.org/uniprot/O14497) and Pfam (http://pfam.xfam.org/protein/O14497) databases showing previously reported ARID1Avariants 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 ARID1Avariants 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.
In autosomal dominant disorders, the co-occurrence of several variants of one causative gene is unusual and considered benign because of the high possibility of the variants occurring in trans configuration, even if they arose
Interestingly, three of the four
This extremely rare case of classic CSS accompanied by a novel
The authors would like to thank the patient and her family for participating in the study.
Lee CG Conceptualization, investigation, and writing-original draft; Ki CS Investigation, formal analysis, writing review and editing.
CONFLICT OF INTEREST
This research was supported by EMBRI Grants 2020EMBRISN0001 from the Eulji University.
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