Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients

Revençu, Nicole; Helaers, Raphaël; Gbaguidi, C.; Dakpe, Stéphanie; François, Geneviève; Devauchelle, Bernard; Bayet, Bénédicte; Vikkula, Miikka

doi:10.3390/genes10100833

Cited by 9 publications

(5 citation statements)

References 40 publications

(55 reference statements)

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“…We also identified a novel missense variant in DLG1 (NM_001366207.1: c.175A > G; NP_001353136.1: p.Thr59Ala) in Family 17. Common variants in DLG1 have been associated with an increased risk for non‐syndromic OFCs (Mostowska et al, 2018) and a novel nonsense variant in DLG1 was previously found in an individual with non‐syndromic discontinuous CLP (Demeer et al, 2019). Lastly, we identified a missense variant of interest in MYH9 in Family 22 (NM_002473.6: c.4745A > G; NP_002464.1: p.Glu1582Gly).…”

Section: Resultsmentioning

confidence: 99%

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Perez

Chung

Head

et al. 2023

American J of Med Genetics Pt A

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Exome sequencing (ES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for ES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, SHROOM3, SMC3, TBX3, and TP63 in six families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs.

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Section: Resultsmentioning

confidence: 99%

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Perez

Chung

Head

et al. 2023

American J of Med Genetics Pt A

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“…FZD1 and its receptor are expressed ventral to the telencephalon and in periocular mesenchyme during the development of the face [ 31 ]. Loss of function variants in DLG1 are associated with non-syndromic discontinuous cleft lip and palate [ 32 ]. MMP25 expression appears to have a crucial role throughout all stages of palatal development [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

Population Genetic Analysis of Ten Geographically Isolated Tibetan Pig Populations

Shang

Tan

et al. 2020

Animals

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Several geographically isolated populations of Tibetan pigs inhabit the high-altitude environment of the Tibetan Plateau. Their genetic relationships, contribution to the pool of genetic diversity, and their origin of domestication are unclear. In this study, whole-genome re-sequencing data from 10 geographically isolated Tibetan pig populations were collected and analyzed. Population genetic analyses revealed limited genetic differentiation among the Tibetan pig populations. Evidence from deleterious variant analysis indicated that population-specific deleterious variants were the major component of all mutational loci. Contribution to the meta-population was largest in the TT (Qinghai-Tibet Plateau) population, based on gene diversity or allelic diversity. Selective sweep analysis revealed numerous genes, including RXFP1, FZD1, OR1F1, TBX19, MSTN, ESR1, MC1R, HIF3A, and EGLN2 which are involved in lung development, hard palate development, coat color, hormone metabolism, facial appearance, and perception of smell. These findings increase our understanding of the origins and domestication of the Tibetan pig, and help optimize the strategy for their conservation.

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“…However, no syndrome caused by germline ARHGAP29 mutations has so far been reported. This is in contrast to several other NsCL/P genes as causative likely pathogenic variants can be identi ed in about 10% of NsCL/P cases in the genes causing SyCL/P [6,38,39]. ARHGAP29 should thus be included in diagnostic genetic testing for NsCL/P, as it may be mutated in around 2% of patients with high penetrance.…”

Section: Discussionmentioning

confidence: 99%

Four Loss of Function Pathogenic Variants in ARHGAP29 in Non-Syndromic Cleft Lip and Palate

Vikkula,

Ranji,

Pairet

et al. 2024

Preprint

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The pathophysiological basis of non-syndromic cleft lip and/or palate (NsCL/P) is still largely unclear. However, exome sequencing (ES) has allowed to associate several genes with NsCL/P, often with reduced penetrance. Among these genes, the Rho GTPase activating protein 29 (ARHGAP29) has been previously implicated in 7 families with NsCL/P. We investigated a cohort of 224 NsCLPs for which no genetic mutation had been identified by diagnostic testing. We used ES and bioinformatic variant filtering and identified four novel likely pathogenic/pathologic variants in ARHGAP29 in four multiplex families. One was a missense variant leading to the substitution of the first methionine with threonine, two were heterozygous frameshift variants leading to a premature termination codon, and the last one was a nonsense variant. All variants were predicted to result in loss of function, either through NMD-mediated mRNA decay, or by truncated ARHGAP29, or by non-translation or abnormal N-terminal initiation of translation of ARHGAP29. The truncated ARHGAP29 proteins would lack the important RhoGAP domain. The variants were not present in the control population databases, and the loss of intolerance score (pLI) of ARHGAP29 is 1.0, suggesting that ARHGAP29 haploinsufficiency is not tolerated. Phenotypes ranged from microform CL to complete bilateral CLP, with one unaffected mutation carriers. These results extend the mutational spectrum of ARHGAP29 and show that it is an important gene underlying variable NsCL/P phenotypes. ARHGAP29 should be included in diagnostic genetic testing for NsCL/P, especially familial cases, as it may be mutated in ⁓2% of patients with high penetrance (88%).

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Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients

Cited by 9 publications

References 40 publications

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Population Genetic Analysis of Ten Geographically Isolated Tibetan Pig Populations

Four Loss of Function Pathogenic Variants in ARHGAP29 in Non-Syndromic Cleft Lip and Palate

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