SMARCE1, a rare cause of Coffin–Siris Syndrome: Clinical description of three additional cases

Abstract

Coffin–Siris syndrome (CSS, MIM 135900), is a well-described, multiple congenital anomaly syndrome characterized by coarse facial features, hypertrichosis, sparse scalp hair, and hypo/aplastic digital nails and phalanges, typically of the 5th digits. Mutations in the BAF (SWI/SNF)-complex subunits (SMARCA4, SMARCE1, SMARCB1, SMARCA2, ARID1B, and ARID1A) have been shown to cause not only CSS, but also related disorders including Nicolaides–Baraitser (MIM 601358) syndrome and ARID1B-intellectual disability syndrome (MIM 614562).At least 200 individuals with CSS have been found to have a mutation in the BAF pathway. However, to date, only three individuals with CSS have been reported to have pathogenic variants in SMARCE1. We report here three additional individuals with clinical features consistent with CSS and alterations in SMARCE1, one of which is novel. The probands all exhibited dysmorphic facial features, moderate developmental and cognitive delay, poor growth, and hypoplastic digital nails/phalanges, including digits not typically affected in the other genes associated with CSS. Two of the three probands had a variety of different organ system anomalies, including cardiac disease, genitourinary abnormalities, feeding difficulties, and vision abnormalities. The 3rd proband has not had further investigative studies. Although an increasing number of individuals are being diagnosed with disorders in the BAF pathway, SMARCE1 is the least common of these genes. This report doubles the number of probands with these mutations, and allows for better phenotypic information of this rare syndrome.

Mutational Landscapes and Phenotypic Spectrum of SWI/SNF-Related Intellectual Disability Disorders

“…SMARCE1 mutations have been described in six patients so far ( Tsurusaki et al, 2012 ; Santen et al, 2013 ; Wieczorek et al, 2013 ; Zarate et al, 2016 ). The phenotype is similar to SMARCB1 -associated SSRIDD and located at the severe end of the SSRIDD spectrum.…”

Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders

“…Six CSS cases have been associated with BAF57 pathogenic mutations, including pTyr73 Cys, pTyr73Ser, pArg105Gln, and pTyr126Asp (Tsurusaki et al, 2012 ; Santen et al, 2013 ; Wieczorek et al, 2013 ; Zarate et al, 2016 ). All of these cases have been reported to present with developmental delay in addition to moderate to severe ID.…”

“…All of these cases have been reported to present with developmental delay in addition to moderate to severe ID. Moreover, they all have the typical features of CSS (Zarate et al, 2016 ). Notably, all these mutations are localized in the high-mobility-group (HMG) DNA binding domain (Figure 2 ).…”

Identification of a de novo splicing variant in the Coffin–Siris gene, SMARCE1, in a patient with Angelman‐like syndrome

“…Using trio whole‐exome sequencing, we identified a novel splice site variant resulting in an in‐frame deletion in the SMARCE1 gene in a patient with an AS‐like phenotype. Pathogenic variants in SMARCE1 and another five genes ( SMARCB1, SMARCA4, SMARCA2, ARID1A, and ARID1B ) encoding subunits of the switch/sucrose non‐fermenting (SWI/SNF) ATP remodeling complex cause CSS (Miyake, Tsurusaki, & Matsumoto, ) which is a rare congenital syndrome characterized by developmental delay, moderate to severe intellectual disability, hypoplasic or absent fifth fingernails or toenails, distinctive facial features, hypertrichosis, sparse scalp hair, and hypotonia (Kosho & Okamoto, ; Santen et al., ; Tsurusaki et al., ; Zarate et al., ).…”

“…To date, only six individuals with SMARCE1 missense pathogenic variants have been reported (Zarate et al., ). Here, we describe the first patient with a pathogenic splicing variant in the CSS gene, SMARCE1 , who had a diagnosis of AS‐like and who presents some clinical features characteristic of AS, which have not been previously associated to CSS.…”