Fine Mapping of 6q23.1 Identifies TULP4 as Contributing to Clefts

Abstract

Objective : The aim of this work was to fine-map the region 6q23.1, which obtained suggestive linkage signal (logarithm of the odds [LOD] score = 2.22 under a recessive model) to cleft lip with or without cleft palate (CL±P) in our previous genome-wide linkage scan to identify possible genetic variants that may contribute to CL±P. Design : We used densely spaced markers spanning the entire 6q23.1 region to test for association with CL±P in a family cohort sample. Setting : Clinical information and DNA samples were obtained from families in the Philippines at their homes or primary health care clinics. Participants : The study sample consisted of 477 subjects (224 females and 253 males), segregating isolated CL±P, from 72 living in the same area in the Philippines. Main Outcome Measure : Overtransmission of alleles to persons born with CL±P. Results : We found statistical evidence of association between a marker of TULP4 (rs651333) with CL±P (P = .00007). Conclusions : Our results further support the linkage results for the chromosome 6q region and reveal a novel candidate gene for CL±P.

Systematic analysis of copy number variants of a large cohort of orofacial cleft patients identifies candidate genes for orofacial clefts

“…In mouse, it is highly expressed during embryogenesis, probably contributing to neural crest cell migration (Lindsay et al 1997 ). A statistically significant association of TULP4 with OFC has been reported in a recent study based on 6q23.1 fine mapping in a cohort of five hundred OFC patients (Vieira et al 2015 ). In our analysis, this gene has been found duplicated in two patients (Supplementary Tables 3, 6).…”

“…We further identified 34 novel candidates which have not previously been associated with OFCs (Supplementary Table 5). Among 27 genes in duplicated CNVs, three of them, DGCR6 , MAPK3 and TULP4 (Table 3 ; Supplementary Tables 2, 5), have been previously associated with orofacial development or proposed as causative for OFC syndromes (Demczuk et al 1996 ; Lindsay and Baldini 1997 ; Yamamoto et al 2003 ; Singh et al 2007 ; Nakamura et al 2009 ; Das Chakraborty et al 2012 ; Vieira et al 2015 ), while the remaining 24 genes are novel candidates (Supplementary Table 5).…”

“…Candidate for 18q deletion syndrome [OMIM#601808] Nishiwaki et al ( 2006 ), Heinonen and Maki ( 2009 ) TSHZ1 6 Deletions Role in Peters-plus syndrome [OMIM#261540] Coré et al ( 2007 ), Dostal et al ( 2009 ) TTC28 3 Deletions Likely gene responsible for Pierre-Robin sequence (including CP) in a case report Davidson et al ( 2012 ) DGCR6 5 Duplications Candidate for DiGeorge syndrome [OMIM*601279] Demczuk et al ( 1996 ), Lindsay and Baldini ( 1997 ), Das Chakraborty et al ( 2012 ) MAPK3 (ERK1) 2 Duplications MAPK pathway involved in craniofacial development. Interactor of ERK2 , whose disruption leads to OFCs in animal models Yamamoto et al ( 2003 ), Singh et al ( 2007 ), Nakamura et al ( 2009 ), O’Brien et al ( 2015 ) TULP4 2 Duplications Statistically significant association in a population-based study Vieira et al ( 2015 ) …”

Characterisation of genetic regulatory effects for osteoporosis risk variants in human osteoclasts

“…The product of the TULP4 gene has not been extensively characterised with regard to a role in bone biology; however, it is thought to be a cytoplasmic protein characterised by a large amino terminus containing a WD40 repeat region and a suppressor of cytokines signalling domain [44]. TULP4 has been implicated in the formation of orofacial clefts [45] and is a body height GWAS locus [32,46]. Mutation in the related gene WDR35 has been implicated in cranioectodermal dysplasia, also known as Sensenbrenner syndrome, an autosomal recessive condition characterised by craniofacial and skeletal abnormalities [47].…”

Racial Variations in Velopharyngeal and Craniometric Morphology in Children: An Imaging Study

“…Chung and Kau (1985) hypothesized that clefting may be related to these morphological cranial variations, which in turn could be related to inherent craniofacial variations on the basis of race. Current research aims to identify the relationship of genetics to cleft markers (Lidral & Moreno, 2005;Vieira et al, 2015). However, to our knowledge, no studies have investigated gene association related to clefting across different racial groups.…”