Genome Scan for Loci Involved in Cleft Lip With or Without Cleft Palate, in Chinese Multiplex Families

Abstract

Cleft lip with or without cleft palate (CL/P) is a common congenital anomaly. Birth prevalences range from 1/500 to 1/1,000 and are consistently higher in Asian populations than in populations of European descent. Therefore, it is of interest to determine whether the CL/P etiological factors in Asian populations differ from those in white populations. A sample of 36 multiplex families were ascertained through probands with CL/P who were from Shanghai. This is the first reported genome-scan study of CL/P in any Asian population. Genotyping of Weber Screening Set 9 (387 short tandem-repeat polymorphisms with average spacing approximately 9 cM [range 1-19 cM]) was performed by the Mammalian Genotyping Service of Marshfield Laboratory. Presented here are the results for the 366 autosomal markers. Linkage between each marker and CL/P was assessed by two-point and multipoint LOD scores, as well as with multipoint heterogeneity LOD scores (HLODs) plus model-free identity-by-descent statistics and the multipoint NPL statistic. In addition, association was assessed via the transmission/disequilibrium test. LOD-score and HLOD calculations were performed under a range of models of inheritance of CL/P. The following regions had positive multipoint results (HLOD > or =1.0 and/or NPL P< or =.05): chromosomes 1 (90-110 cM), 2 (220-250 cM), 3 (130-150 cM), 4 (140-170 cM), 6 (70-100 cM), 18 (110 cM), and 21 (30-50 cM). The most significant multipoint linkage results (HLOD > or =2.0; alpha=0.37) were for chromosomes 3q and 4q. Associations with P< or =.05 were found for loci on chromosomes 3, 5-7, 9, 11, 12, 16, 20, and 21. The most significant association result (P=.009) was found with D16S769 (51 cM).

A specific requirement for PDGF-C in palate formation and PDGFR-α signaling

“…PDGF-C is a latent growth factor with proteolytic activation 1 , and the processing enzyme might be controlled by the other CLP-associated genes that may indirectly connect to PDGF-C signaling. Notably, a 30-cM region on human chromosome 4, where the PDGFC gene maps, shows strong linkage association with CLP 26 , and our unpublished clinical genetic data further suggest a potential link between PDGFC gene polymorphism and CLP. …”

Progress toward discerning the genetics of cleft lip

“…The identification of geneenvironment interactions will be greatly aided by the ongoing National Study of Birth Defects Prevention [90]. Finally, new analytic strategies are being developed and tested to identify genetic epistasis and address the known heterogeneity of genetically complex traits [91].…”

CRISPLD2: a novel NSCLP candidate gene

“…Egfr, Bmp4, Bmpr1 and Folbp1) (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Eight genome scans have identified regions that may potentially harbor NSCLP susceptibility genes (19)(20)(21)(22)(23)(24)(25). In 2000, Prescott et al (26) identified nine chromosomal regions that are associated with orofacial clefting in their Caucasian NSCLP sib-pair population.…”