Cleft Lip with or without Cleft Palate via the ARHGAP29 Gene

Pathogenic variants in the ARHGAP29 gene are associated with non-syndromic (isolated) cleft lip with or without cleft palate (CL/P). CL/P is the most common type of congenital craniofacial anomaly identified in newborns, occurring at a rate of 1-2 per 1,000 live births (IPDTOC Working Group. 2011. PubMed ID: 20507242; Mai et al. 2014. PubMed ID: 25399767; Dixon et al. 2011. PubMed ID: 21331089). CL/P may be identified on prenatal ultrasound or at birth. Individuals with non-syndromic CL/P may have difficulties feeding, speaking, and hearing, and may require surgery, dental treatment, speech therapy, audiology, and psychological counseling (Burg et al. 2016. PubMed ID: 26973535). Genetic testing may aide in establishing diagnosis and prognosis, and may assist in reproductive planning.

ARHGAP29-associated CL/P is inherited in an autosomal dominant manner and displays incomplete penetrance and variable expressivity (Leslie et al. 2012. PubMed ID: 23008150; Liu et al. 2017. PubMed ID: 28029220; Savastano et al. 2017. PubMed ID: 27350171). Whilst no de novo pathogenic variants have been reported in the ARHGAP29 gene to date, pathogenic variants have been reported to arise de novo in other genes associated with orofacial clefting (Peyrard-Janvid et al. 2005. PubMed ID: 16160700; Peyrard-Janvid et al. 2014. PubMed ID: 24360809). Pathogenic missense and loss of function variants have been reported (Leslie et al. 2012. PubMed ID: 23008150; Butali et al. 2014. PubMed ID: 25081408; Chandrasekharan and Ramanathan. 2014. PubMed ID: 25512736; Letra et al. 2014. PubMed ID: 25163644; Leslie et al. 2015. PubMed ID: 25704602; Gowans et al. 2016. PubMed ID: 27369588; Liu et al. 2017. PubMed ID: 28029220). To date, no pathogenic copy number variants (CNVs) or large chromosomal rearrangements have been associated with ARHGAP29-related CL/P. Estimates from gene constraint models suggest this gene is intolerant of loss of function variation, but relatively tolerant of missense variation (https://gnomad.broadinstitute.org/gene/ENSG00000137962). However caution should be used when considering these metrics due to the variable penetrance and expressivity of ARHGAP29-related CL/P.

ARHGAP29 encodes a GTPase-activating protein, which is involved in the regulation of small GTP binding proteins that affect actin re-arrangement, cell-cell and cell-matrix adhesion, and cell spreading, all of which are critical for craniofacial development (Saras et al. 1997. PubMed ID: 9305890; Myagmar et al. 2005. PubMed ID: 15752761; Post et al. 2013. PubMed ID: 23798437; Post et al. 2015. PubMed ID: 25963656). Expression has been detected in several tissues, including the palatal shelves and oral epithelium during craniofacial development in mouse embryos (Saras et al. 1997. PubMed ID: 9305890; Leslie et al. 2012. PubMed ID: 23008150; Paul et al. 2017. PubMed ID: 28817352).

ARHGAP29 is one of many genes associated with CL/P (Kousa et al. 2017. PubMed ID: 27933721). Please refer to our Cleft Lip/Cleft Palate Panel for additional genes associated with orofacial clefting.

Pathogenic variants in the ARHGAP29 gene are emerging as a rare cause of non-syndromic CL/P, having been reported in cases-control studies, and a limited number of isolated cases and multigenerational families (Leslie et al. 2012. PubMed ID: 23008150; Butali et al. 2014. PubMed ID: 25081408; Chandrasekharan and Ramanathan. 2014. PubMed ID: 25512736; Letra et al. 2014. PubMed ID: 25163644; Leslie et al. 2015. PubMed ID: 25704602; Gowans et al. 2016. PubMed ID: 27369588; Liu et al. 2017. PubMed ID: 28029220). Clinical sensitivity is difficult to estimate for ARHGAP29. In one study, rare ARHGAP29 variants were detected in 7 of 1,440 cases with non-syndromic CL/P (0.5%) and absent in controls (Leslie et al. 2012. PubMed ID: 23008150).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the ARHGAP29 genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome)