Research: Congenital diaphragmatic hernia in Coffin Siris syndrome: Further evidence from two cases

Am J Med Genet A

. 2022 Nov 23.

 doi: 10.1002/ajmg.a.63054. Online ahead of print.

Congenital diaphragmatic hernia in Coffin Siris syndrome: Further evidence from two cases

Martina Rimoldi 1Berardo Rinaldi 1Roberta Villa 1Jacopo Cerasani 2Benedetta Beltrami 1Maria Iascone 3Rosamaria Silipigni 4Simona Boito 5Silvana Gangi 2Lorenzo Colombo 2Matteo Porro 6Claudia Cesaretti 1Maria Francesca Bedeschi 1

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Coffin-Siris Syndrome (CSS) is a rare multi-system dominant condition with a variable clinical presentation mainly characterized by hypoplasia/aplasia of the nail and/or distal phalanx of the fifth digit, coarse facies, hirsutism/hypertrichosis, developmental delay and intellectual disability of variable degree and growth impairment. Congenital anomalies may include cardiac, genitourinary and central nervous system malformations whereas congenital diaphragmatic hernia (CDH) is rarely reported. The genes usually involved in CSS pathogenesis are ARID1B (most frequently), SMARCA4, SMARCB1, ARID1A, SMARCE1, DPF2, and PHF6. Here, we present two cases of CSS presenting with CDH, for whom Whole Exome Sequencing (WES) identified two distinct de novo heterozygous causative variants, one in ARID1B (case 1) and one in SMARCA4 (case 2). Due to the rarity of CDH in CSS, in both cases the occurrence of CDH did not represent a predictive sign of CSS but, on the other hand, prompted genetic testing before (case 1) or independently (case 2) from the clinical hypothesis of CSS. We provide further evidence of the association between CSS and CDH, reviewed previous cases from literature and discuss possible functional links to related conditions.

Keywords: ARID1B; Coffin-Siris syndrome; SMARCA4; congenital diaphragmatic hernia; whole exome sequencing.

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