TMEM218 dysfunction causes ciliopathies, including Joubert and Meckel syndromes

Abstract

Summary The Joubert-Meckel syndrome spectrum is a continuum of recessive ciliopathy conditions caused by primary cilium dysfunction. The primary cilium is a microtubule-based, antenna-like organelle that projects from the surface of most human cell types, allowing them to respond to extracellular signals. The cilium is partitioned from the cell body by the transition zone, a known hotspot for ciliopathy-related proteins. Despite years of Joubert syndrome (JBTS) gene discovery, the genetic cause cannot be identified in up to 30% of individuals with JBTS, depending on the cohort, sequencing method, and criteria for pathogenic variants. Using exome and targeted sequencing of 655 families with JBTS, we identified three individuals from two families harboring biallelic, rare, predicted-deleterious missense TMEM218 variants. Via MatchMaker Exchange, we identified biallelic TMEM218 variants in four additional families with ciliopathy phenotypes. Of note, four of the six families carry missense variants affecting the same highly conserved amino acid position 115. Clinical features included the molar tooth sign (N = 2), occipital encephalocele (N = 5, all fetuses), retinal dystrophy (N = 4, all living individuals), polycystic kidneys (N = 2), and polydactyly (N = 2), without liver involvement. Combined with existing functional data linking TMEM218 to ciliary transition zone function, our human genetic data make a strong case for TMEM218 dysfunction as a cause of ciliopathy phenotypes including JBTS with retinal dystrophy and Meckel syndrome. Identifying all genetic causes of the Joubert-Meckel spectrum enables diagnostic testing, prognostic and recurrence risk counseling, and medical monitoring, as well as work to delineate the underlying biological mechanisms and identify targets for future therapies.

Genotype–phenotype correlates in Joubert syndrome: A review

“…(Bachmann-Gagescu, Brancati et al, 2007;Brooks et al, 2018;Chaki et al, 2012;Edvardson et al, 2010;Kar, Phadke, Das Bhowmik, & Dalal, 2018;Lambacher et al, 2016;Powell et al, 2020;Srour et al, 2015;Suzuki et al, 2016;Valente et al, 2006;Van De Weghe et al, 2021;Wang et al, 2018). In the UW cohort, a retinal phenotype was observed in all patients with CEP290-related JS, an association which remained statistically significant even after Bonferroni correction (odds ratio…”

“…Within the large JS cohort by the University of Washington (UW), encephalocele (usually occipital) was present in 8% of individuals, significantly correlating with pathogenic variants in either OFD1 or TCTN2 (Bachmann‐Gagescu, Dempsey, et al, 2015). However, this malformation has been occasionally identified in patients carrying pathogenic variants in a large number of other JS genes, including all the commonly mutated ones (Ben‐Salem, Al‐Shamsi, Gleeson, Ali, & Al‐Gazali, 2014; Cantagrel et al, 2008; Edvardson et al, 2010; Gorden et al, 2008; Lee et al, 2012; Suzuki et al, 2016; Van De Weghe et al, 2021).…”

“…The retinal disease can range from the extremely severe Leber congenital amaurosis (LCA) to pigmentary retinopathies evident at fundus oculi examination or milder forms of retinal dystrophy detectable only by electroretinogram, with variably conserved vision (Wang et al, 2018). This phenotype has been associated with a long list of genes, yet the two commonest players clearly are CEP290 and AHI1 (Bachmann‐Gagescu, Dempsey, et al, 2015; Brancati et al, 2007; Brooks et al, 2018; Chaki et al, 2012; Edvardson et al, 2010; Kar, Phadke, Das Bhowmik, & Dalal, 2018; Lambacher et al, 2016; Lee, Silhavy, Lee, et al, 2012; Powell et al, 2020; Srour et al, 2015; Suzuki et al, 2016; Valente et al, 2006; Van De Weghe et al, 2021; Wang et al, 2018). In the UW cohort, a retinal phenotype was observed in all patients with CEP290 ‐related JS, an association which remained statistically significant even after Bonferroni correction (odds ratio [OR] 22.9, confidence intervals [CI] 6.7–78.4; p < .0001) (Bachmann‐Gagescu, Dempsey, et al, 2015), and in eight out of 16 JS individuals with AHI1 pathogenic variants.…”

“…Several other genes have been rarely associated with renal disease in smaller reports (Alkanderi et al, 2018; Beaudin, Klein, Rouleau, & Dupre, 2017; Beck et al, 2014; Ben‐Salem et al, 2014; Chaki et al, 2012; Field et al, 2012; Huppke et al, 2015; Latour et al, 2020; Lee, Silhavy, Lee, et al, 2012; Shen et al, 2020; Slaats et al, 2016; Srour et al, 2012; Stephen et al, 2017; Thomas et al, 2014; Tuz et al, 2014; Van De Weghe et al, 2021). Among them, RPGRIP1L deserves a special mention, as Suzuki et al reported 26 out of 30 mutated patients (86.7%) showing a renal phenotype.…”

“…The NIH cohort, where polydactyly was present in 13 out of 99 JS individuals (13%), substantially confirmed the significant positive correlation between polydactyly and CPLANE1 (Vilboux, Doherty, et al, 2017). Besides this association, polydactyly (mainly postaxial) has been described in several reports in association with the vast majority of JS known genes, including biallelic missense variants in SUFU (Bachmann‐Gagescu, Dempsey, et al, 2015; Bachmann‐Gagescu, Phelps, et al, 2015; Brancati et al, 2009; De Mori et al, 2017; Epting et al, 2020; Hardee et al, 2017; Kar et al, 2018; Kroes et al, 2016; Lambacher et al, 2016; Latour et al, 2020; Lee, Silhavy, Lee, et al, 2012; Powell et al, 2020; Radha Rama Devi et al, 2020; Shaheen et al, 2019; Stephen et al, 2017; Thomas et al, 2014; Van De Weghe et al, 2021; Zhang et al, 2017; Zhang, Qu, et al, 2021; Zhongling, Guoming, Yanhui, & Xiaoru, 2021).…”