Evidence for an association between Coffin‐Siris syndrome and congenital diaphragmatic hernia

Abstract

Coffin-Siris syndrome (CSS) is an autosomal dominant neurodevelopmental syndrome that can present with a variety of structural birth defects. Pathogenic variants in 12 genes have been shown to cause CSS. Most of these genes encode proteins that are a part of the mammalian switch/sucrose non-fermentable (mSWI/SNF; BAF) complex. An association between genes that cause CSS and congenital diaphragmatic hernia (CDH) has been suggested based on case reports and the analysis of CSS and CDH cohorts. Here, we describe an unpublished individual with CSS and CDH, and we report additional clinical information on four published cases. Data from these individuals, and a review of the literature, provide evidence that deleterious variants in ARID1B, ARID1A, SMARCB1, SMARCA4, SMARCE1, ARID2, DPF2, and SMARCC2, which are associated with CSS types 1-8, respectively, are associated with the development of CDH. This suggests that additional genetic testing to identify a separate cause of CDH in an individual with CSS may be unwarranted, and that comprehensive genetic testing for individuals with non-isolated CDH should include an evaluation of CSS-related genes. These data also suggest that the mSWI/SNF (BAF) complex may play an important role in diaphragm development.

Elucidating the clinical and molecular spectrum ofSMARCC2-associated NDD in a cohort of 65 affected individuals

“…14,15 To date, reports of SMARCC2 variants have been mostly part of individual case reports or large NDD studies with limited clinical information. [9][10][11][12][13]16 In an attempt to better characterize the clinical and molecular spectrum of SMARCC2-associated NDD, a large cohort of 65 cases was collected, including 41 novel individuals with de novo or inherited variants, whose clinical and molecular findings were systematically described, and 24 previously published individuals, whose data were thoroughly curated. Additionally, Human Phenotype Ontology (HPO) and automated facial recognition were used to investigate genotype-phenotype correlations between nontruncating and LGD variants, and structural modeling as well as functional assays to investigate missense variants.…”

“…8,12 Three novel missense substitutions (c.2697G>T p.(Leu899Phe), c.640A>G p.(Thr214Ala), and c.1327C>T p.(Arg443Trp)) and one previously described splice variant (c.1651-2A>G p.?) 13 could not be further classified due to lack of conclusive evidence (no strong segregation information, recurrence, or strong effects in functional studies). Thus, carriers Ind-03, Ind-06, Ind-40, and Gofin_Subject 5 were excluded from further clinical analysis.…”

“…[2][3][4][5][6][7] Recent studies reporting affected individuals with mainly de novo missense/in-frame and a few likely gene-disrupting (LGD) pathogenic variants in another BAF-subunit, SMARCC2 (BAF170, MIM *601734), expanded the spectrum of BAF-related NDDs. [8][9][10][11][12][13] Machol et al described a cohort of 15 cases with variable clinical manifestations resembling CSS and NCBRS. 8 The Online Mendelian Inheritance in Man (OMIM) database now classifies the SMARCC2-associated phenotype as Coffin-Siris syndrome 8 (MIM #601734).…”

First‐trimester prenatal diagnosis of Coffin‐Siris syndrome‐related congenital diaphragmatic hernia: The role of exome sequencing in determining genetic etiology

“…It seems that somatic variants are not associated with CDH, and de novo germline variants of CDH‐associated genes can be found in 10%–30% of CDH patients, including those causing isolated CDH and those causing non‐isolated CDH 7 . Gofin et al 8 recently reported an association between genes that cause CSS and CDH. They provided the evidence in their own 5 patients and additional 12 cases from a review of the literature.…”