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Evidence for craniofacial enhancer variation underlying nonsyndromic cleft lip and palate
Ist Teil von
Human genetics, 2020-10, Vol.139 (10), p.1261-1272
Ort / Verlag
Berlin/Heidelberg: Springer Berlin Heidelberg
Erscheinungsjahr
2020
Quelle
SpringerLink Journals - AutoHoldings
Beschreibungen/Notizen
Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect for which only ~ 20% of the underlying genetic variation has been identified. Variants in noncoding regions have been increasingly suggested to contribute to the missing heritability. In this study, we investigated whether variation in craniofacial enhancers contributes to NSCLP. Candidate enhancers were identified using VISTA Enhancer Browser and previous publications. Prioritization was based on patterning defects in knockout mice, deletion/duplication of craniofacial genes in animal models and results of whole exome/whole genome sequencing studies. This resulted in 20 craniofacial enhancers to be investigated. Custom amplicon-based sequencing probes were designed and used for sequencing 380 NSCLP probands (from multiplex and simplex families of non-Hispanic white (NHW) and Hispanic ethnicities) using Illumina MiSeq. The frequencies of identified variants were compared to ethnically matched European (CEU) and Los Angeles Mexican (MXL) control genomes and used for association analyses. Variants in mm427/
MSX1
and hs1582/
SPRY1
showed genome-wide significant association with NSCLP (
p
≤ 6.4 × 10
–11
).
In silico
analysis showed that these enhancer variants may disrupt important transcription factor binding sites. Haplotypes involving these enhancers and also mm435/
ABCA4
were significantly associated with NSCLP, especially in NHW (
p
≤ 6.3 × 10
–7
). Importantly, groupwise burden analysis showed several enhancer combinations significantly over-represented in NSCLP individuals, revealing novel NSCLP pathways and supporting a polygenic inheritance model. Our findings support the role of craniofacial enhancer sequence variation in the etiology of NSCLP.