A de novo splicing variant supports the candidacy of TLL1 in ASD pathogenesis


Alanzi T, Alhashem A, Dagriri K, Alzahrani F, Alkuraya FS.

Eur J Hum Genet. 2020 Apr;28(4):525-528. doi: 10.1038/s41431-019-0524-0. Epub 2019 Sep 30.

PMID: 31570783

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Congenital heart disease (CHD) is the most common type of birth defects with family- and population-based studies supporting a strong hereditary component. Multifactorial inheritance is the rule although a growing number of Mendelian forms have been described including candidates that have yet to be confirmed independently. TLL1 is one such candidate that was proposed in the etiology of atrial septal defect (ASD). We describe a girl with congenitally corrected transposition of the great arteries (ccTGA) and ASD secundum whose whole-exome sequencing (WES) revealed a de novo splicing (c.1379-2A>G) variant in TLL1 as well as an inherited truncating variant in NODAL. The identification of this dual molecular diagnosis both supports the candidacy of TLL1 in ASD pathogenesis and highlights the power of WES in revealing multilocus cardiac phenotypes.