The Role of De Novo Variants in Formation of Human Anorectal Malformations

Abstract

Anorectal malformations (ARM) represent a rare birth defect of the hindgut that occur in approximately 1 in 3000 live births. Around 60% of ARM occur with associated anomalies including defined genetic syndromes and associations with chromosomal aberrations. The etiology of ARM is heterogeneous, with the individual environmental or genetic risk factors remaining unknown for the majority of cases. The occurrence of familial ARM and previous epidemiologic analysis suggest autosomal dominant inheritance in a substantial subset of ARM patients. The implicated mortality and reduced fecundity in patients with ARM would lead to allele loss. However, mutational de novo events among the affected individuals could compensate for the evolutionary pressure. With the implementation of exome sequencing, array-based molecular karyotyping and family-based rare variant analyses, the technologies are available to identify the respective factors. This review discusses the identification of disease-causing variants among individuals with ARM. It highlights the role of mutational de novo events.

Novel inheritedCDX2variant segregating in a family with diverse congenital malformations of the genitourinary system

“…They encompass diverse anomalies of varying severity, primarily affecting the genitourinary system. However, involvement of other organs including spine (and spinal cord), gastrointestinal tracts, musculoskeletal system (limbs/ digits), and orofacial system have also been reported, particularly in syndromic ARM such as VACTERL (Dworschak, van Rooij et al 2021).…”

“…Ours is the first study that reports multiple affected patients in a family who harbor a pathogenic CDX2 variant that was inherited from a father (Individual I-1) who reported no such anomalies. This raises the possibility incomplete penetrance or variable expressivity of the phenotype, a phenomenon well-documented in this group of disorders (Dworschak, van Rooij et al 2021). We have not excluded the possibility that the father is affected -as he was not examined by a clinician -but he selfreports as healthy and had no history of surgeries.…”

“…Incomplete penetrance of phenotypes is a well-documented phenomenon in syndromic and nonsyndromic ARM (Schwoebel, Hirsig et al 1984, Dworschak, van Rooij et al 2021, Stevens, Stumpel et al 2022). Although CDX2 is not currently associated with human disease according to the OMIM database (MIM #600297), there is growing evidence of its critical role in gastrointestinal development (Suh, Chen et al 1994, Beck 2004, Chawengsaksophak, de Graaff et al 2004, Beck and Stringer 2010.…”

Anorectal Malformations are Part of the Phenotypic Spectrum of Coffin-Siris Syndrome: Case Report and Review of the Literature

“…Monogenic variants explain up to 1/3 of syndromic ARMs, and are very heterogeneous [8]. The genes involved in syndromic ARMs include but are not limited to: ADNP (Helsmoortel-van der Aa syndrome), BBS1 (Bardet-Biedl syndrome 1), CHD7 (CHARGE syndrome), CREBBP (Rubinstein-Taybi syndrome 1), EP300 (Rubinstein-Taybi syndrome 2), FANCC (Fanconi anemia group C), GLI3 (Pallister-Hall syndrome), KDM6A ( Kabuki syndrome 2), MID1 (Opitz G/BBB syndrome), MNX1 (Currarino syndrome), SALL1 (Townes-Brocks syndrome), SALL4 (Duane-radial ray syndrome ), and SETD2 (SETD2-related disorders) [1,9,10] Coffin-Siris syndrome (CSS) is a well-known genetic disorder characterized by developmental delay and/or intellectual disability, hypoplastic to absent fifth fingernails and fifth distal phalanges, coarse facial appearance, and other variable features including hypotonia, slow growth, hypertrichosis, sparse scalp hair, feeding difficulties, and organ malformations [11]. CSS is caused by Disclaimer/Publisher's Note: The statements, opinions, and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s).…”