<i>FAT4</i> identified as a potential modifier of orofacial cleft laterality

Curtis, Sarah W.; Chang, Daniel; Sun, Meng; Epstein, Michael P.; Murray, Jeffrey C.; Feingold, Eleanor; Beaty, Terri H.; Weinberg, Seth M.; Marazita, Mary L.; Lipinski, Robert J.; Carlson, Jenna C.; Leslie, Elizabeth J.

doi:10.1002/gepi.22420

Cited by 16 publications

(12 citation statements)

References 50 publications

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“…We observed a yield of 17.6% in CP and 9.09% in CLP cases, but only a 2.80% yield in CL cases, the latter of which was not significantly different from controls. Our results reinforce the etiologic heterogeneity in OFC subtypes observed recently from multiple genome-wide association studies 45; 58-61 and extend it to rare variants. They also suggest that when choosing to pursue clinical sequencing, proband cleft type might be a consideration.…”

Section: Discussionsupporting

confidence: 90%

Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting

Perez¹,

Curtis²,

Sanchis-Juan³

et al. 2022

Preprint

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Orofacial clefts (OFCs) are common craniofacial birth defects including cleft lip (CL), cleft lip with cleft palate (CLP), and cleft palate (CP). The etiological heterogeneity of OFCs complicates clinical diagnostics as it is not always readily apparent if the cause is Mendelian, environmental, or multifactorial. Although sequencing could aid diagnosis, it is not commonly used for the 60-70% of OFC cases that appear isolated or lack a strong family history. We aimed to estimate the diagnostic yield evaluating 503 genes using whole-genome sequencing data from 841 cases and 294 controls. After curating variants, we evaluated them according to the American College of Medical Genetics pathogenicity criteria blinded to case-control status. We found 'likely pathogenic' variants in 9.04% of cases and 1.36% of controls (p<0.0001), which was almost exclusively driven by dominant variants in autosomal genes. The yield was highest in CP (17.6%) and CLP (9.09%) cases, while CL (2.80%) cases were not significantly different from controls. We identified 'likely pathogenic' variants in cases in 39 genes, underscoring the genetic heterogeneity of OFCs. Notably, nine genes, including CTNND1, IRF6, and COL2A1, were recurrently mutated, accounting for more than half of the yield (occurring in 4.64% of OFC cases). Most reviewed variants (60.6%) were 'variants of uncertain significance' (VUS) and were more frequent in cases (p=7.31 x 10-4), but no individual gene showed a significant excess of VUS. Cumulatively, these results underscore the etiological heterogeneity of OFCs and suggest clinical sequencing could help reduce the diagnostic gap in OFC etiology.

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Section: Discussionsupporting

confidence: 90%

Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting

Perez¹,

Curtis²,

Sanchis-Juan³

et al. 2022

Preprint

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“…The idea that genetically related individuals also tend to have the same type of OFC more often than different types of OFCs, has been rarely utilized in running GWASs of OFC subtypes. Individual level phenotypic heterogeneity in terms of laterality and gender‐effects has been analyzed to investigate genetic heterogeneity in previous studies on the Pitt‐OFC subjects (Curtis, Chang, Lee, et al, 2021; Curtis, Chang, Sun, et al, 2021). However, these variables were not incorporated in our study—as our sample is already subdivided into smaller samples based on the OFC subtypes observed in families, further subsetting by gender and/or laterality would lead to subsets too small for running GWAS.…”

Section: Discussionmentioning

confidence: 99%

Genome‐wide association study of multiethnic nonsyndromic orofacial cleft families identifies novel loci specific to family and phenotypic subtypes

Mukhopadhyay

Feingold

Moreno‐Uribe

et al. 2022

Genetic Epidemiology

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Nonsyndromic orofacial clefts (OFCs) are among the most common craniofacial birth defects worldwide, and known to exhibit phenotypic and genetic heterogeneity. Cleft lip plus cleft palate (CLP) and cleft lip only (CL) are commonly combined together as one phenotype (CL/P), separately from cleft palate alone. In comparison, our study analyzes CL and CLP separately. A sample of 2218 CL and CLP cases, 4537 unaffected relatives of cases, and 2673 pure controls with no family history of OFC were selected from the Pittsburgh Orofacial Cleft (Pitt‐OFC) multiethnic study.genome‐wide association studies were run for seven specific phenotypes created based on the cleft type(s) observed within these families, as well as the combined CL/P phenotype. Five novel genome‐wide significant associations, 3q29 (rs62284390), 5p13.2 (rs609659), 7q22.1 (rs6465810), 19p13.3 (rs628271), and 20q13.33 (rs2427238), and nine associations (p ≤ 1.0E−05) within previously confirmed OFC loci—PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, ARID3B, NTN1, TANC2 and the WNT9B:WNT3 gene cluster—were observed. We also found that single nucleotide polymorphisms within a subset of the associated loci, both previously known and novel, differ substantially in terms of their effects across cleft‐ or family‐specific phenotypes, indicating not only etiologic differences between CL and CLP, but also genetic heterogeneity within each of the two OFC subtypes.

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“…Furthermore, Liu et al ( 95 ) described an interaction between the PRICKLE1 and FOCAD loci for cranial base width underlying a variance quantitative trait locus (QTL) at PRICKLE1 . With respect to craniofacial disease, three distinct modifiers of nsCL/P subtypes have been discovered in the last few years: the FAT4 locus for cleft laterality ( 34 ), the PAX1 locus for bilaterality versus unilaterality ( 33 ), and a third locus for cleft palate ( 16 ).…”

Section: Common Variation In Craniofacial Shapementioning

confidence: 99%

Decoding the Human Face: Progress and Challenges in Understanding the Genetics of Craniofacial Morphology

Naqvi

Hoskens

Wilke

et al. 2022

Annu. Rev. Genom. Hum. Genet.

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Variations in the form of the human face, which plays a role in our individual identities and societal interactions and exhibits extreme forms in a broad range of craniofacial syndromes and birth defects, have fascinated both geneticists and developmental biologists. Here, we review our current understanding of the genetics underlying variation in craniofacial morphology and dysmorphology, synthesizing decades of progress on Mendelian syndromes in addition to more recent results from genome-wide association studies of human facial shape and disease risk. We also discuss the various approaches used to phenotype and quantify facial shape, which are of particular importance due to the complex, multipartite nature of the craniofacial form. We close by discussing how experimental studies have contributed and will further contribute to our understanding of human genetic variation and then proposing future directions and applications for the field. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 23 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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FAT4 identified as a potential modifier of orofacial cleft laterality

Cited by 16 publications

References 50 publications

Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting

Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting

Genome‐wide association study of multiethnic nonsyndromic orofacial cleft families identifies novel loci specific to family and phenotypic subtypes

Decoding the Human Face: Progress and Challenges in Understanding the Genetics of Craniofacial Morphology

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