Titel: Pathogenic variants in LEF1 cause a syndrome combining ectodermal dysplasia and limb malformations by disrupting WNT signaling
ID: W9-003
Art: Invited talk
Redezeit: 15 min
Session: Workshop 9
Monogenic Syndromes

Referent: Muhammad Sajid Hussain (Köln/DE)

Abstract - Text


Ectrodactyly ectodermal dysplasia without cleft lip/palate (MIM 129810) is reported with clinical manifestation of split-hand/foot malformation accompanied by ectodermal anomalies like hypotrichosis and abnormal dentition. This disorder has received insufficient attention in the past. We recruited 12 individuals from 5 unrelated families manifesting a syndrome with variable expression of limb malformations and/or ectodermal dysplasia. The phenotypic spectrum includes various limb malformations, such as radial ray defects, polydactyly or split hand/foot, and ectodermal dysplasia in some individuals. High-throughput sequencing allowed the identification of 4 novel LEF1 variants. These variants were monoallelic in 11 affected individuals and biallelic in one. LEF1 encodes a transcription factor acting downstream of the WNT-β-Catenin signaling pathway. By performing pulldown assays, we have shown that out of four, only the p.M23dup variant impaired interaction with β-catenin due to its location in a highly conserved β-catenin binding domain of LEF-1. Whole transcriptomic profiling further confirmed that Wnt/ β-catenin signaling pathway is impaired. We have seen significant differential expression of transcripts already known as downstream targets of the Wnt/ β-catenin signaling pathway and HOX family — both Wnt and HOX are crucial for embryonic developmental events. Our functional data show that two molecular mechanisms are at play: haploinsufficiency or loss of DNA-binding are responsible for a mild to moderate phenotype, while loss of β-Catenin binding due to biallelic variants is associated with a severe phenotype. Our findings establish mono- and biallelic variants in LEF1 as a cause for a syndrome comprising limb malformations and ectodermal dysplasia.