Most WBS patients have a >1 Mb deletion on one of their chromosomes 7 in q11 but except for elastin, whose haploinsufficiency causes the cardiovascular malformations, it is unknown which genes in the deletion area contribute to the phenotype.
Animal studies have shown that knockout of the transforming growth factor beta-2 (TGFβ2) gene results in diverse cardiovascular malformations and that its unregulated expression is involved in the pathogenesis of heart defects.
Our analyses revealed 28 candidate variants in 27 genes, including 17 genes not previously associated with a human CVM disorder, and revealed diverse patterns of inheritance among LOF carriers, including 9 confirmed de novo variants in both novel and newly described human CVM candidate genes (ACVR1, JARID2, NR2F2, PLRG1, SMURF1) as well as established syndromic CVM genes (KMT2D, NF1, TBX20, ZEB2).
Maternal phenylketonuria (MPKU) is a syndrome including cardiovascular malformations (CVMs), microcephaly, intellectual impairment, and small size for gestational age, caused by in-utero exposure to elevated serum phenylalanine (Phe) due to PKU in the mother.
Through biological and in silico analyses, our study suggests an association between SIX1/EYA1 mutations and cardiovascular malformations, SIX1/EYA1 mutations might be partially responsible for CTDs.
The results suggest that cardiac phenotypes are very variable in patients with the terminal deletion of chromosome 4q and that haploinsufficiency of the dHAND is not necessarily associated with CVMs.
Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice.