Phenotypic manifestations of C5orf42 pathogenic variants

Abstract

Joubert syndrome is a genetic disease with an autosomal-recessive or X-linked inheritance pattern caused by pathogenic variants in at least 35 genes, all encoding structures of the primary cilium involved in signaling pathways that coordinate the normal development of the kidneys, retina, brain, liver and skeletal system. The symptoms can consist in cystic renal disease and renal dystrophy, oculomotor apraxia, global developmental delay, hypotonia evolving into ataxia, skeletal and endocrine abnormalities, abnormal breathing patterns and congenital hepatic fibrosis, with the neurologic and ophthalmologic manifestations appearing early in life. The diagnostic hallmark is “the molar tooth sign”, a malformation of the brainstem and cerebellum easily identifiable using brain imaging techniques. As Joubert syndrome is a highly heterogeneous disease with a large type of phenotypes, it is oftentimes underdiagnosed. This article presents a case of Joubert syndrome type 17, a rare syndrome with many features overlapping orofaciodigital syndrome type VI. Adding to the rarity of this disease, our patient is homozygous and heterozygous for two pathogenic variants in C5orf42, with one located upstream of the other, thus manifesting the phenotype of a compound heterozygous in this gene. We believe that the presentation of this rare syndrome is useful to the pediatric practice by facilitating a fast diagnosis of these patients, which helps provide genetic counselling to the patients and their families.