Two novel genes TOX3 and COL21A1 in large extended Malay families with nonsyndromic cleft lip and/or palate

BACKGROUND: Nonsyndromic cleft lip and/or palate is one of the most common human birth defects worldwide that affects the lip and/or palate. The incidence of clefts varies among populations through ethnic, race, or geographical differences. The focus on Malay nonsyndromic cleft lip and/or palate (NSCL/P) is because of a scarce report on genetic study in relation to this deformity in Malaysia. We are interested to discuss about the genes that are susceptible to cause orofacial cleft formation in the family.

METHODS: Genome-wide linkage analysis was carried out on eight large extended families of NSCL/P with the total of 91 individuals among Malay population using microarray platform. Based on linkage analyses findings, copy number variation (CNV) of LPHN2, SATB2, PVRL3, COL21A1, and TOX3 were identified in four large extended families that showed linkage evidence using quantitative polymerase chain reaction (qPCR) as for a validation purpose. Copy number calculated (CNC) for each genes were determined with Applied Biosystems CopyCallerTM Software v2.0. Normal CNC of the target sequence expected was set at two.

RESULTS: Genome-wide linkage analysis had discovered several genes including TOX3 and COL21A1 in four different loci 4p15.2-p16.1, 6p11.2-p12.3, 14q13-q21, and 16q12.1. There was significant decreased, p