Haploinsufficiency of <i>GRHL2</i> is associated with orofacial clefting in humans

Orofacial clefts (OFCs) are one of the most common structural birth defects, with the prevalence of OFC varying across populations, and studies on the causes of OFCs in diverse populations are necessary, but still limited. We analyzed whole genome sequencing data on 419 parent-child trios from the Philippines, a population with a particularly high rate of OFC. To identify novel genes for OFCs, we studied both common variation and de novo variants (DNVs). We identified a significant enrichment in both loss-of-function (N = 62; P = 8.34 × 10-5) and protein-altering DNVs (N = 394; P = 1.49 × 10-7) among OFC probands. Among the genes individually enriched for DNVs was GRHL2 (P = 6.60 × 10-6), where there were two DNVs, a stop-gain and a frameshift deletion. We then queried OFC trios from other cohorts in the Gabriella Miller Kids First program (total N = 1254) and GeneMatcher and identified an 89 kb de novo deletion in GRHL2 and a de novo 8q22.3 microdeletion with one breakpoint in GRHL2. Additionally, within the common variant analyses we found significant gene x gene interactions with GRHL2. GRHL2 is a conserved transcription factor involved in embryonic development, with truncating mutations causing autosomal dominant progressive hearing loss and missense variants causing autosomal recessive ectodermal dysplasia. Heterozygous variation in its homolog, GRHL3, causes Van der Woude syndrome and isolated cleft palate. Additionally, mice deficient for either Grhl2 or Grhl3 have craniofacial anomalies, including facial and palatal clefts, strongly supporting GRHL2 as a risk locus for OFCs.

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Publication Details

Journal
Human Molecular Genetics
Published
2025-10-21
DOI
https://doi.org/10.1093/hmg/ddaf163
Primary Topic
Cleft Lip and Palate Research
Type
article
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article

Haploinsufficiency of GRHL2 is associated with orofacial clefting in humans

Harrison Brand, Sebastian Dworkin, Carmencita David Padilla, Alba Sanchis-Juan et al.
Human Molecular Genetics
Cleft Lip and Palate Research
article

Haploinsufficiency of GRHL2 is associated with orofacial clefting in humans

Harrison Brand, Sebastian Dworkin, Carmencita David Padilla, Alba Sanchis-Juan, Jenna C. Carlson, Florian Erger, John R. Shaffer, Jeffrey C. Murray, Seth M. Weinberg, Michael P. Epstein, Lina M. Moreno Uribe, Sarah W. Curtis, Chih-Ting Yang, Eleanor Feingold, Mary L. Marazita, Elizabeth J. Leslie, Max Krause, Clara Velmans, Christian Netzer, Terri H. Beaty, Katherine Singleton
article en

Abstract

Orofacial clefts (OFCs) are one of the most common structural birth defects, with the prevalence of OFC varying across populations, and studies on the causes of OFCs in diverse populations are necessary, but still limited. We analyzed whole genome sequencing data on 419 parent-child trios from the Philippines, a population with a particularly high rate of OFC. To identify novel genes for OFCs, we studied both common variation and de novo variants (DNVs). We identified a significant enrichment in both loss-of-function (N = 62; P = 8.34 × 10-5) and protein-altering DNVs (N = 394; P = 1.49 × 10-7) among OFC probands. Among the genes individually enriched for DNVs was GRHL2 (P = 6.60 × 10-6), where there were two DNVs, a stop-gain and a frameshift deletion. We then queried OFC trios from other cohorts in the Gabriella Miller Kids First program (total N = 1254) and GeneMatcher and identified an 89 kb de novo deletion in GRHL2 and a de novo 8q22.3 microdeletion with one breakpoint in GRHL2. Additionally, within the common variant analyses we found significant gene x gene interactions with GRHL2. GRHL2 is a conserved transcription factor involved in embryonic development, with truncating mutations causing autosomal dominant progressive hearing loss and missense variants causing autosomal recessive ectodermal dysplasia. Heterozygous variation in its homolog, GRHL3, causes Van der Woude syndrome and isolated cleft palate. Additionally, mice deficient for either Grhl2 or Grhl3 have craniofacial anomalies, including facial and palatal clefts, strongly supporting GRHL2 as a risk locus for OFCs.

Human Molecular GeneticsVol. 34(24)
Broad Institute (US), University of Iowa (US), Department of Health (PH), Johns Hopkins University (US), Emory University (US), University of Pittsburgh (US), La Trobe University (AU), Massachusetts General Hospital (US), Balaji Dental & Craniofacial Hospital (IN), Department of Health (TW), University Hospital Cologne (DE), Center for Systems Biology (US), University of the Philippines Manila (PH)
Openalex Percentile: Top 66%
Cleft Lip and Palate Research
DOIOpen Access PDFOpenAlex
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