Nonsyndromic cleft lip with or without cleft palate: Increased burden of rare variants within Gremlin-1, a component of the bone morphogenetic protein 4 pathway.
BACKGROUND
The genes Gremlin-1 (GREM1) and Noggin (NOG) are components of the bone morphogenetic protein 4 pathway, which has been implicated in craniofacial development. Both genes map to recently identified susceptibility loci (chromosomal region 15q13, 17q22) for nonsyndromic cleft lip with or without cleft palate (nsCL/P). The aim of the present study was to determine whether rare variants in either gene are implicated in nsCL/P etiology.


METHODS
The complete coding regions, untranslated regions, and splice sites of GREM1 and NOG were sequenced in 96 nsCL/P patients and 96 controls of Central European ethnicity. Three burden and four nonburden tests were performed. Statistically significant results were followed up in a second case-control sample (n = 96, respectively). For rare variants observed in cases, segregation analyses were performed.


RESULTS
In NOG, four rare sequence variants (minor allele frequency < 1%) were identified. Here, burden and nonburden analyses generated nonsignificant results. In GREM1, 33 variants were identified, 15 of which were rare. Of these, five were novel. Significant p-values were generated in three nonburden analyses. Segregation analyses revealed incomplete penetrance for all variants investigated.


CONCLUSIONS
Our study did not provide support for NOG being the causal gene at 17q22. However, the observation of a significant excess of rare variants in GREM1 supports the hypothesis that this is the causal gene at chr. 15q13. Because no single causal variant was identified, future sequencing analyses of GREM1 should involve larger samples and the investigation of regulatory elements.
Institute of Human Genetics, University of Bonn, Bonn, Germany; Klinikverbund St. Antonius und St. Josef, Wuppertal, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
Taofik
T
Al Chawa
Kerstin U
KU
Ludwig
Heide
H
Fier
Bernd
B
Pötzsch
Rudolf H
RH
Reich
Gül
G
Schmidt
Bert
B
Braumann
Nikolaos
N
Daratsianos
Anne C
AC
Böhmer
Hannah
H
Schuencke
Margrieta
M
Alblas
Nadine
N
Fricker
Per
P
Hoffmann
Michael
M
Knapp
Christoph
C
Lange
Markus M
MM
Nöthen
Elisabeth
E
Mangold
D000483:Alleles; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D002971:Cleft Lip / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D002972:Cleft Palate / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005787:Gene Frequency; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005858:Germany / Q000453:epidemiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D016366:Open Reading Frames; D019683:Penetrance; D015398:Signal Transduction; D020506:Untranslated Regions; D044465:White People; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D020506:Untranslated Regions; D000099176:Noggin Protein; C525809:BMP4 protein, human; C486399:GREM1 protein, human
GREM1; NOG; SNP; cleft lip; cleft palate; re-sequencing