X‐linked markers in the <scp>D</scp>uchenne muscular dystrophy gene associated with oral clefts

Patel, Poorav J.; Beaty, Terri H.; Ruczinski, Ingo; Murray, Jeffrey C.; Marazita, Mary L.; Munger, Ronald G.; Hetmanski, Jacqueline B.; Wu, Tao; Murray, Tanda; Rose, Michael; Redett, Richard J.; Jin, Sheng Chih; Lie, Rolv Terje; Wu-Chou, Yah Huei; Wang, Hong; Ye, Xiaoqian; Yeow, Vincent; Chong, Samuel S.; Jee, Sun Ha; Shi, Bing; Scott, Alan F.

doi:10.1111/eos.12025

Cited by 12 publications

(33 citation statements)

References 23 publications

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“…If confirmed in future studies, the apparent lack of difference in Amerindian ancestry evaluated by autosomal markers between patients with CL±P and controls from Patagonia could indicate an aetiological contribution to CL±P linked to genes that are present in mitochondrial DNA or the X‐chromosome, which result in inheritance patterns completely different from that of autosomal chromosomes. Genome‐wide studies have identified variants in regions and genes of the X‐chromosome that are associated with CL±P . The association between variants of the dystrophin gene ( DMD ; Xp21.2‐21.1) and CL±P was recently confirmed in a sample of 26 families, with a high contribution of Amerindian ancestry and from the same Patagonian population evaluated in the present study.…”

Section: Discussionsupporting

confidence: 61%

Analysis of the genetic ancestry of patients with oral clefts from South American admixed populations

Vieira-Machado

Carvalho

Silva

et al. 2016

European J Oral Sciences

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Increased susceptibility to cleft lip, with or without cleft palate (CL±P) has been observed in South America, as related to Amerindian ancestry, using epidemiological data, uniparental markers, and blood groups. In this study, it was evaluated whether this increased risk remains when Amerindian ancestry is estimated using autosomal markers and considered in the predictive model. Ancestry was estimated through genotyping 62 insertion and deletion (INDEL) markers in sample sets of patients with CL±P, patients with cleft palate (CP), and controls, from Patagonia in southern Argentina and Belém in northern Brazil. The Amerindian ancestry in patients from Patagonia with CL±P was greater than in controls although it did not reach statistical significance. The European ancestry in patients with CL±P from Belém and in patients with CP from Belém and Patagonia was higher than in controls and statistically significant for patients with CP who were from Belém. This high contribution of European genetic ancestry among patients with CP who were from Belém has not been previously observed in American populations. Our results do not corroborate the currently accepted risks for CL±P and CP estimated by epidemiological studies in the North American populations and probably reflect the higher admixture found in South American ethnic groups when compared with the same ethnic groups from the North American populations.

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Section: Discussionsupporting

confidence: 61%

Analysis of the genetic ancestry of patients with oral clefts from South American admixed populations

Vieira-Machado

Carvalho

Silva

et al. 2016

European J Oral Sciences

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“…Given the predicted association of X‐linked genes with syndromic forms of OC and the gender differences among OC types, we tested whether genetic variation on the X chromosome could be relevant to the etiology of isolated CL±P. Of the three X‐linked genes previously reported to be associated with X‐linked syndromes and isolated CL±P [midline 1 ( MID1 ) , oral‐facial‐digital syndrome 1 ( OFD1 ) , and DMD ], only the association between DMD and isolated CL±P was confirmed in the present study. Using the Illumina Human610‐Quad platform, which includes 14,486 X‐chromosome markers, Patel et al .…”

Section: Resultsmentioning

confidence: 52%

“…Using the Illumina Human610‐Quad platform, which includes 14,486 X‐chromosome markers, Patel et al . identified six SNPs (rs5928207, rs5928208, rs6631759, rs5971698, rs5928214, and rs5972815) in DMD that were associated with OC in European and Asian populations; when the subjects were stratified by ethnicity, stronger signals were obtained for the Asian population. Using a different type of analysis, we also found an association between DMD and CL±P.…”

Section: Resultsmentioning

confidence: 99%

“… argued against an actual role of the product of the DMD gene in the etiology of OC, and proposed that interactions might occur between distant SNPs within DMD . The authors demonstrated that the four SNPs of the DMD haplotype, significantly associated with OCs in the Asian population, were effectively uncorrelated with one another, and they argued against the possibility that all four SNPs were correlated with one high‐risk allele of a single, as‐yet‐unidentified, causal gene . Nonetheless, we cannot dismiss the possibility that the DMD haplotype identified in the present study may be a chance finding, and that only one of the four SNPs is actually in LD with a causal variation.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, Patel et al . conducted an investigation of 14,486 single nucleotide polymorphisms (SNPs) spanning the X chromosome and found an association between the dystrophin gene ( DMD ; Xp21.2–21.1) and CL±P, mainly in Asian populations, even after correction for multiple comparisons.…”

mentioning

confidence: 99%

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Family‐based genome‐wide association study in Patagonia confirms the association of the DMD locus and cleft lip and palate

Fonseca

Carvalho

Poletta

et al. 2015

European J Oral Sciences

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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.

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Genome‐wide interaction studies identify sex‐specific risk alleles for nonsyndromic orofacial clefts

Carlson

Nidey

Butali

et al. 2018

Genetic Epidemiology

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Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene-by-sex (G x S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome-wide joint tests of the genetic (G) and G x S effects genome-wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test (p < 1.00 × 10−5) by examining the G x S effects from the same model. Out of the 133 loci with suggestive results (p < 1.00 × 10−5) for the joint test, we observed one genome-wide significant G x S effect in the 10q21 locus (rs72804706; p = 6.69 × 10−9; OR = 2.62 [1.89, 3.62]) and 16 suggestive G x S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects.

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X‐linked markers in the Duchenne muscular dystrophy gene associated with oral clefts

Cited by 12 publications

References 23 publications

Analysis of the genetic ancestry of patients with oral clefts from South American admixed populations

Analysis of the genetic ancestry of patients with oral clefts from South American admixed populations

Family‐based genome‐wide association study in Patagonia confirms the association of the DMD locus and cleft lip and palate

Genome‐wide interaction studies identify sex‐specific risk alleles for nonsyndromic orofacial clefts

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