Expanding the genetic landscape of oral‐facial‐digital syndrome with two novel genes

Abstract

Oral-facial-digital syndromes (OFDS) are a heterogeneous and rare group of Mendelian disorders characterized by developmental abnormalities of the oral cavity, face, and digits caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates organ patterning and growth. OFDS is inherited both in an X-linked dominant, X-linked recessive, and autosomal recessive manner. Importantly, though many of the causal genes for OFDS have been identified, up to 40% of OFD syndromes are of unknown genetic basis. Here we describe three children with classical presentations of OFDS including lingual hamartomas, polydactyly, and characteristic facial features found by exome sequencing to harbor variants in causal genes not previously associated with OFDS. We describe a female with hypothalamic hamartoma, urogenital sinus, polysyndactyly, and multiple lingual hamartomas consistent with OFDVI with biallelic pathogenic variants in CEP164, a gene associated with ciliopathy-spectrum disease, but never before with OFDS. We additionally describe two unrelated probands with postaxial polydactyly, multiple lingual hamartomas, and dysmorphic features both found to be homozygous for an identical TOPORS missense variant, c.29 C>A; (p.Pro10Gln). Heterozygous TOPORS pathogenic gene variants are associated with autosomal dominant retinitis pigmentosa, but never before with syndromic ciliopathy. Of note, both probands are of Dominican ancestry, suggesting a possible founder allele.Ciliopathy syndromes are rare Mendelian disorders caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates proper organ patterning and growth (Berbari et al., 2009;Fry et al., 2014). Oral-facial-digital syndromes (OFDS) represent a heterogenous group of ciliopathies, characterized by the core features of oral cavity malformations, such as tongue hamartomas, cleft palate, lobulated tongue, and hyperplastic frenula, craniofacial dysmorphisms such as down-slanted palpebral

Deletion of CEP164 in mouse photoreceptors post-ciliogenesis interrupts ciliary intraflagellar transport (IFT)

“…CEP164( X1460WextX57 ), identified in a child with Leber congenital amaurosis (LCA) [ 13 ], causes a read-through of the stop-codon X1460, adding 57 foreign amino acid residues to the CEP164 C-terminus. Biallelic pathogenic variants in CEP164 are causative of oral-facial-digital syndromes (OFDS) [ 15 ].…”

TOPORS as a novel causal gene for Joubert syndrome

“…Data analysis was done using the PLINK software (Chang et al, 2015;Purcell et al, 2007). Regions of homozygosity (ROH) were first identified in the index patient and were subsequently aligned to ROH identified in the previously published proband (Strong et al, 2021).…”

Essential Roles of Efferent Duct Multicilia in Male Fertility

“…The role of CEP164 in spermatogenesis remains to be explored. Mutations in CEP164 have been identified in a host of ciliopathy patients including nephronophthisis, BBS, PCD, and oral-facial-digital syndrome [134][135][136][137][138], but male reproductive phenotypes have not been reported.…”