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High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations

Abstract

Evidence suggests that genetic factors contribute to the development of anorectal malformations (ARMs). However, the etiology of the majority of ARMs cases remains unclear. Exome sequencing (ES) may be underutilized in the diagnostic workup of ARMs due to uncertainty regarding its diagnostic yield. In a clinical database of ~17,000 individuals referred for ES, we identified 130 individuals with syndromic ARMs. A definitive or probable diagnosis was made in 45 of these individuals for a diagnostic yield of 34.6% (45/130). The molecular diagnostic yield of individuals who initially met criteria for VACTERL association was lower than those who did not (26.8% vs 44.1%; p = 0.0437), suggesting that non-genetic factors may play an important role in this subset of syndromic ARM cases. Within this cohort, we identified two individuals who carried de novo pathogenic frameshift variants in ADNP, two individuals who were homozygous for pathogenic variants in BBS1, and single individuals who carried pathogenic or likely pathogenic variants in CREBBP, EP300, FANCC, KDM6A, SETD2, and SMARCA4. The association of these genes with ARMs was supported by previously published cases, and their similarity to known ARM genes as demonstrated using a machine learning algorithm. These data suggest that ES should be considered for all individuals with syndromic ARMs in whom a molecular diagnosis has not been made, and that ARMs represent a low penetrance phenotype associated with Helsmoortel-van der Aa syndrome, Bardet-Biedl syndrome 1, Rubinstein-Taybi syndromes 1 and 2, Fanconi anemia group C, Kabuki syndrome 2, SETD2-related disorders, and Coffin-Siris syndrome 4.

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Fig. 1: Machine learning allows all RefSeq genes to be ranked based on their similarity to genes known to cause ARMs.

Data availability

The data generated during this study can be found within the published article and its Supplementary Files. All variants reported here have been submitted to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/; SUB11464682).

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Funding

This work was supported, in part, by National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development grant R01HD098458 to DAS.

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Contributions

DAS conceived the study. RBD wrote the first draft of the manuscript. CAS and PL were responsible for the machine learning. XZ was responsible for providing updated variant interpretation based on ACMG criteria. JAR obtained and provided clinical and molecular data. RBD and DAS analyzed clinical and molecular data. All authors reviewed, edited, and approved the final draft.

Corresponding author

Correspondence to Daryl A. Scott.

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Competing interests

The Department of Molecular & Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics.

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This study was approved by the institutional review board of Baylor College of Medicine (protocol H-47546) and was conducted in accordance with the ethical standards of this institution’s committee on human research and international standards.

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Belanger Deloge, R., Zhao, X., Luna, P.N. et al. High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01255-y

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