Genetic analysis of rare coding mutations of CELSR1–3 in congenital heart and neural tube defects in Chinese people

Abstract

The planar cell polarity (PCP) pathway is critical for proper embryonic development of the neural tube and heart. Mutations in these genes have previously been implicated in the pathogenesis of neural tube defects (NTDs), but not in congenital heart defects (CHDs) in humans. We systematically identified the mutation patterns of CELSR1-3 , one family of the core PCP genes, in human cohorts composed of 352 NTD cases, 412 CHD cases, and matched controls. A total of 72 disease-specific rare novel coding mutations were identified, of which 37 were identified in CHD cases, and 36 were identified in NTD patients. Most of these mutations differed between the two cohorts, as only one novel missense mutation in CELSR1 (c.2609G>A p.P870L) was identified in both NTD and CHD patients. Both in vivo and in vitro assays revealed that CELSR1 P870L is a gain-of-function mutation. It up-regulates not only the PCP pathway, but also canonical WNT signaling in cells, and also induced both NTDs and CHDs in Zebrafish embryos. As almost equal numbers of mutations were identified in each cohort, our results provided the first evidence that mutations in CELSR genes are as likely to be associated with CHDs as with NTDs, although the specific mutations differ between the two cohorts. Such differences in mutation panels suggested that CELSRs might be regulated differently during the development of these two organ systems.

Genetic contribution of retinoid-related genes to neural tube defects

“…Genetic studies of mice have identified more than 240 genes involved in neural tube closure (Harris & Juriloff, 2010;Wilde, Petersen, & Niswander, 2014;Wilson, & Maden, 2005) and this information has provided a framework to explore the genetic causes of NTDs in humans over the past decade (Chen et al, 2017;De Marco et al, 2014;Kibar et al, 2007;Qiao et al, 2016). Genes that function in particular pathways involved in planar cell polarity (PCP), ciliogenesis, the glycine cleavage system and one-carbon metabolism have been explored in a relatively large number of cases (Allache et al, 2015;Cai & Shi, 2014;De Marco et al, 2014;Dowdle et al, 2011;Hopp et al, 2011;Jones, Fiozzo, Waters, McKnight, & Brown, 2014;Kibar et al, 2007;Lei et al, 2013;Lei et al, 2014;Lei et al, 2010;Marini et al, 2011;Merello et al, 2015;Miao et al, 2016;Narisawa et al, 2012;Qiao et al, 2016;Roberson et al, 2015;Robinson et al, 2012;Shaheen et al, 2015;Yang et al, 2013;Zhang et al, 2015). PCP gene variants have been associated with the most severe NTD phenotype, craniorachischisis, as well as more limited NTDs such as myelomeningocele.…”

Increasing evidence of hereditary lymphedema caused by CELSR1 loss‐of‐function variants

“…CELSR1 is important for kidney growth and differentiation, and for rostrocaudal patterning. Patients with CELSR1 variants can have significant congenital heart defects (Qiao et al, ) and renal malformations (Brzóska et al, ), two features that occur in 80% (Tafazoli et al, ) and 10% (Roberts, Allanson, Tartaglia, & Gelb, ) of Noonan patients, respectively.…”

Genetic and functional analysis of SHROOM1-4 in a Chinese neural tube defect cohort

“…Sequencing was performed on Illumina GAII (Illumina, San Diego, CA, USA) platform using the paired-end program. Variant calling and annotation was performed using previously established methods (Qiao et al 2016). Coding variants were classified as synonymous, missense, LoF (loss of function, including splice acceptor/donor, stop gained/lost, initiator codon and frameshift indels) and others using Variant Effect Predictor (VEP) (McLaren et al 2010).…”