Hydrolethalus syndrome (HLS) is a lethal, autosomal recessive ciliopathy caused by the mutation of the conserved centriole protein HYLS1. How HYLS1 controls centriole function is poorly understood. Here, we show that mice harboring the HYLS1 disease mutation die shortly after birth and exhibit developmental defects that recapitulate several manifestations of HLS. These phenotypes arise from a loss of centriole integrity that causes tissue-specific defects in cilia assembly and function. We show that HYLS1 is recruited to the centriole by CEP120 and stabilizes the localization of centriole inner scaffold proteins that ensure the integrity of the centriolar microtubule wall. The HLS disease mutation reduced the centriole localization of HYLS1 and caused degeneration of the centriole distal end. We propose that tissue-specific defects in centriole integrity caused by the HYLS1 mutation prevent ciliogenesis and contribute to HLS phenotypes.

This is a fatal case of multiple complicated congenital anomalies displaying several symptoms consistent with hydrolethalus syndrome. The newborn's phenotype is characterized by a combination of serious anatomical abnormalities such as open-book cerebral hemispheres, defective lobulation of the lungs (one lobe on the left, two on the right), a smaller right kidney, a smooth cerebral surface, and a specific keyhole-shaped defect in the skull base, primarily associated with hydrocephalus.

KIAA0586 variants have been associated with a wide range of ciliopathies, mainly Joubert syndrome (JS, OMIM #616490) and short-rib thoracic dysplasia syndrome (SRTD, OMIM #616546). However, the hypothesis that this gene is involved with hydrolethalus syndrome (HSL, OMIM #614120) and orofaciodigital syndrome IV (OMIM #258860) has already been raised. Ciliopathies' clinical features are often overlapped despite differing in phenotype severity. Besides KIAA0586, HYLS1 and KIF7 are also known for being causative of ciliopathies, indicating that all three genes may have similar or converging genomic pathways. Overall, the genotypic and phenotypic spectrum of ciliopathies becomes wider and conflicting while more and more new variants are added to this group of disorders' molecular pot. In this case report we discuss the first Brazilian individual clinically diagnosed with hydrolethalus syndrome and molecular findings that demonstrate the role of KIAA0586 as a causative gene of a group of genetic disorders. Also, recent reports on individuals with intronic and exonic variants combined leading to ciliopathies support our patient's molecular diagnosis. At the same time, we discuss variable expressivity and overlapping features in ciliopathies.

Joubert syndrome (JS) is an inherited neurodevelopmental ciliopathy with wide clinical and genetic heterogeneity, whose paradigmatic sign is a peculiar cerebellar and brainstem malformation known as the 'molar tooth sign'. Recessive pathogenic variants in the HYLS1 gene are associated with hydrolethalus syndrome (HLS), a severe disorder characterised by multiple developmental defects leading to intrauterine or perinatal death. However, HYLS1 biallelic variants were also reported in three individuals with JS.Here, we report a fourth patient with a purely neurological JS carrying two compound heterozygous missense variants in the HYLS1 gene. Notably, while all patients with lethal HLS had both variants falling within the highly conserved HYLS-1 Box, the four patients with milder JS phenotype featured at least one variant external to this evolutionary conserved domain, suggesting a possible correlation between the mutation site and the severity of the phenotype.

Mutations in the KIF7 gene have been implicated in autosomal recessive conditions such as Joubert syndrome, acrocallosal syndrome, and fetal hydrolethalus, as well as in retinal degeneration and other ocular manifestations due to their effect on primary cilia. In this study, we report that the full-field electroretinogram (ERG) test showed non-recordable scotopic ERG responses, while photopic ERG responses were diminished bilaterally. This is a case report of a 62-year-old female patient with painless, progressive vision loss in both eyes. Fundus examination revealed a pale optic nerve head, vessel attenuation, and macular thinning without peripheral pigmentary changes. The full-field electroretinogram (ERG) test showed non-recordable scotopic ERG responses, while photopic ERG responses were diminished bilaterally. Based on these ocular findings, the patient was clinically diagnosed with retinitis pigmentosa (RP) sine pigmento. Genetic testing identified a pathogenic heterozygous mutation in the KIF7 gene with the variant c.61C>T (p.Arg21*). Our case suggests that this pathologic variant may be associated with RP sine pigmento. Further studies are warranted to better understand the role of the KIF7 gene in retinal dystrophies.