Family-based genome-wide association study in Patagonia confirms the association of the DMD locus and cleft lip and palate.
The etiology of cleft lip with or without cleft palate (CL±P) is complex and heterogeneous, and multiple genetic and environmental factors are involved. Some candidate genes reported to be associated with oral clefts are located on the X chromosome. At least three genes causing X-linked syndromes [midline 1 (MID1), oral-facial-digital syndrome 1 (OFD1), and dystrophin (DMD)] were previously found to be associated with isolated CL±P. We attempted to confirm the role of X-linked genes in the etiology of isolated CL±P in a South American population through a family-based genome-wide scan. We studied 27 affected children and their mothers, from 26 families, in a Patagonian population with a high prevalence of CL±P. We conducted an exploratory analysis of the X chromosome to identify candidate regions associated with CL±P. Four genomic segments were identified, two of which showed a statistically significant association with CL±P. One is an 11-kb region of Xp21.1 containing the DMD gene, and the other is an intergenic region (8.7 kb; Xp11.4). Our results are consistent with recent data on the involvement of the DMD gene in the etiology of CL±P. The MID1 and OFD1 genes were not included in the four potential CL±P-associated X-chromosome genomic segments.
Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.|ECLAMC (Latin-American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil.
Renata F
RF
Fonseca
Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.|ECLAMC (Latin-American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil.|ECLAMC at LEMC (Laboratory of Congenital Malformation Epidemiology), Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
Flávia M
FM
de Carvalho
ECLAMC (Latin-American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil.|ECLAMC at LEMC (Laboratory of Congenital Malformation Epidemiology), Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.|ECLAMC at CEMIC (Center for Medical Education and Clinical Research) and CONICET (National Council for Scientific and Technical Investigation), Buenos Aires, Argentina.
Fernando A
FA
Poletta
CIPF (Computational Genomics Department, Centro de Investigación Príncipe Felipe); and CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras), Valencia, Spain.
David
D
Montaner
CIPF (Computational Genomics Department, Centro de Investigación Príncipe Felipe); and CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras), Valencia, Spain.
Joaquin
J
Dopazo
(In memoriam), ECLAMC at Hospital Zonal El Bolsón, El Bolsón, Argentina.
Juan C
JC
Mereb
Genetics Division, National Cancer Institute, Rio de Janeiro, Brazil.
Miguel A M
MAM
Moreira
Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.|Genetics Division, National Cancer Institute, Rio de Janeiro, Brazil.
Hector N
HN
Seuanez
Departments of Oral Biology and Pediatric Dentistry and Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Alexandre R
AR
Vieira
ECLAMC (Latin-American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil.|ECLAMC at LEMC (Laboratory of Congenital Malformation Epidemiology), Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.|ECLAMC at CEMIC (Center for Medical Education and Clinical Research) and CONICET (National Council for Scientific and Technical Investigation), Buenos Aires, Argentina.
Eduardo E
EE
Castilla
Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.|ECLAMC (Latin-American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil.
Iêda M
IM
Orioli
DMD gene; South America; case-mother duo; cleft lip with or without cleft palate; oral cleft