The expanding phenotype of OFD1‐related disorders: Hemizygous loss‐of‐function variants in three patients with primary ciliary dyskinesia

Abstract

Background OFD1 has long been recognized as the gene implicated in the classic dysmorphology syndrome, oral‐facial‐digital syndrome type I (OFDSI). Over time, pathogenic variants in OFD1 were found to be associated with X‐linked intellectual disability, Joubert syndrome type 10 (JBTS10), Simpson‐Golabi‐Behmel syndrome type 2 (SGBS2), and retinitis pigmentosa. Recently, OFD1 pathogenic variants have been implicated in primary ciliary dyskinesia (PCD), a disorder of the motile cilia with a phenotype that includes recurrent oto‐sino‐pulmonary infections, situs abnormalities, and decreased fertility. Methods We describe three male patients with PCD who were found to have hemizygous pathogenic variants in OFD1, further supporting that PCD is part of a clinical spectrum of OFD1‐related disorders. In addition, we provide a review of the available clinical literature describing patients with OFD1 variants and highlight the phenotypic variability of OFD1‐related disease. Results Some individuals with hemizygous OFD1 variants have PCD, either apparently isolated or in combination with other features of OFD1‐related disorders. Conclusion As clinicians consider the presence or absence of conditions allelic at OFD1, PCD should be considered part of the spectrum of OFD1‐related disorders. Understanding the OFD1‐related disease spectrum may allow for more focused genetic testing and more timely management of treatable sequelae.

Emerging Genotype-Phenotype Relationships in Primary Ciliary Dyskinesia

“…Neurologic manifestations such as intellectual disability, hydrocephalus or ventriculomegaly are increasingly seen in people with overlapping features of motile and primary ciliopathies. Individuals with one or more of these symptoms can have variants in the genes OFD1 , MCIDAS, or FOXJ1 [ 45 , 86 , 98 ]. Indeed, single mutations in FOXJ1 , a transcription factor that regulates cilia gene expression, reduce the number of motile cilia, and clinically associated with hydrocephalus, recurrent respiratory infections, and laterality defects [ 86 ].…”

Healthcare recommendations for Joubert syndrome

“…Rare individuals with JS additionally have restrictive lung disease due to co-existing skeletal dysplasia such as Jeune syndrome (Halbritter et al, 2013;Lehman et al, 2010;Shaheen et al, 2015;Tuz et al, 2014). Several male individuals with hemizygous OFD1 variants have been reported to have recurrent respiratory infections similar to individuals with primary ciliary dyskinesia (unpublished; Budny et al, 2006;Coene et al, 2009;Hannah et al, 2019); however, additional research is required to determine whether individuals with JS are at increased risk for respiratory issues due to abnormal mucociliary clearance. Clinicians should consider evaluation for primary ciliary dyskinesia in individuals with JS and recurrent respiratory infections.…”

A Case of Primary Ciliary Dyskinesia Caused by a Mutation in OFD1, Which Was Diagnosed Owing to Clostridium difficile Infection

“…We identified an OFD1 gene mutation in our patient. The OFD1 gene, located on chromosome Xp22.2, has long been recognized as a gene involved in the classic dysmorphology syndrome oral-facial-digital syndrome type I (OFDSI), which causes dysmorphic features of the mouth, face, and digits [8]. Pathogenic variants of OFD1 were found to be associated with X-linked intellectual disability, Joubert syndrome type 10 (which results in morphological abnormalities of the cerebellum and brainstem), Simpson-Golabi-Behmel syndrome type 2 (which results in macrocephaly, intellectual disability, and obesity), and retinitis pigmentosa.…”