Coffin-Siris syndrome: phenotypic evolution of a novel SMARCA4 mutation

Abstract

Coffin-Siris Syndrome (CSS) is an intellectual disability disorder caused by mutation of components of the SWI/SNF chromatin-remodeling complex. We describe the evolution of the phenotypic features for a male patient with CSS from birth to age 7 years and 9 months and by review of reported CSS patients, we expand the phenotype to include neonatal and infantile hypertonia and upper airway obstruction. The propositus had a novel de novo heterozygous missense mutation in exon 17 of SMARCA4 (NM_001128849.1:c.2434C>T (NP_001122321.1:p.Leu812Phe)). This is the first reported mutation within motif Ia of the SMARCA4 SNF2 domain. In summary, SMARCA4-associated CSS is a pleiotropic disorder in which the pathognomic clinical features evolve and for which the few reported individuals do not demonstrate a clear genotype-phenotype correlation.

Keywords: choanal stenosis; chromatin remodeling; expressivity; intellectual disability; scoliosis.

FIG. 1

Clinical photographs of the propositus from birth to age 7 years and 9 months. Frontal and profile photographs from birth (A, F), 1 year (B, G), 5 years (C, H), 6 years (D, I), and 7 years (E, J) show the evolution of CSS-associated features. Anterior and posterior views of the hands at age 4 years 2 months (K, L) and a posterior view at age 6 years 8 months (M) show the distal fingers and hypoplastic fingernails. Photograph of the propositus’ left foot at age 7 years and 9 months (N) shows the hypoplastic toenails.

FIG. 2

T1 weighted brain MRI images of the propositus showing the partial agenesis of the corpus callosum (arrows). Images are from scans performed at birth (A) and at age 3 years (B).

FIG. 3

The propositus carries a novel de novo heterozygous missense mutation in SMARCA4. (A) Structure of the SMARCA4 gene and the motifs encoded by the exons. The propositus’ mutation c.2434C>T was located in exon 17, which encodes a portion of the SNF2 domain. (B) The propositus was heterozygous for c.2434C>T. This mutation was not detected in the blood DNA of any other family members. (C) The mutation p.Leu812Phe alters an amino acid conserved across species. (D) Amino acid sequence of the SMARCA4 SNF2 domain with the location of CSS-associated mutations represented by arrowheads. The conserved motifs characteristic of SNF2 domains are highlighted in orange and labeled below the sequence. The amino acids of the Walker A (WA, phosphate binding) and Walker B (WB, magnesium binding) sites are represented by black bars over the sequence. Compared to reported CSS-associated SMARCA4 mutations (black arrows), the propositus’ mutation (blue arrow) is the only one located in motif Ia.