Genomewide scan for nonsyndromic cleft lip and palate in multigenerational Indian families reveals significant evidence of linkage at 13q33.1-34.
Nonsyndromic cleft lip with or without cleft palate (CL-P) is a common congenital anomaly with incidence ranging from 1 in 300 to 1 in 2,500 live births. We analyzed two Indian pedigrees (UR017 and UR019) with isolated, nonsyndromic CL-P, in which the anomaly segregates as an autosomal dominant trait. The phenotype was variable, ranging from unilateral to bilateral CL-P. A genomewide linkage scan that used approximately 10,000 SNPs was performed. Nonparametric linkage (NPL) analysis identified 11 genomic regions (NPL>3.5; P<.005) that could potentially harbor CL-P susceptibility variations. Among those, the most significant evidence was for chromosome 13q33.1-34 at marker rs1830756 (NPL=5.57; P=.00024). This was also supported by parametric linkage; MOD score (LOD scores maximized over genetic model parameters) analysis favored an autosomal dominant model. The maximum LOD score was 4.45, and heterogeneity LOD was 4.45 (alpha =100%). Haplotype analysis with informative crossovers enabled the mapping of the CL-P locus to a region of approximately 20.17 cM (7.42 Mb) between SNPs rs951095 and rs726455. Thus, we have identified a novel genomic region on 13q33.1-34 that harbors a high-risk variant for CL-P in these Indian families.
Radhakrishna
Uppala
U
Green Cross Blood Bank and Genetic Research Centre, Paldi, India. uppala@medecine.unige.ch
Ratnamala
Uppala
U
Gaines
Mathew
M
Beiraghi
Soraya
S
Hutchings
David
D
Golla
Jeffrey
J
Husain
Syed A
SA
Gambhir
Prakash S
PS
Sheth
Jayesh J
JJ
Sheth
Frenny J
FJ
Chetan
Ghati K
GK
Naveed
Mohammed
M
Solanki
Jitendra V
JV
Patel
Uday C
UC
Master
Dilipkumar C
DC
Memon
Rafiq
R
Antonarakis
Gregory S
GS
Antonarakis
Stylianos E
SE
Nath
Swapan K
SK
D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D008040:Genetic Linkage; D015894:Genome, Human; D006239:Haplotypes; D006801:Humans; D007194:India; D010375:Pedigree; D020161:Physical Chromosome Mapping