Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome

A rare syndrome was first described in 1997 in a 17-year-old male patient presenting with Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia (RHYNS). In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance. U...

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Bibliographic Details
Published in:European journal of human genetics : EJHG 2018-09, Vol.26 (9), p.1266-1271
Main Authors: Brancati, Francesco, Camerota, Letizia, Colao, Emma, Vega-Warner, Virginia, Zhao, Xiangzhong, Zhang, Ruixiao, Bottillo, Irene, Castori, Marco, Caglioti, Alfredo, Sangiuolo, Federica, Novelli, Giuseppe, Perrotti, Nicola, Otto, Edgar A
Format: Article
Language:English
Subjects:
Adult
Alleles
Bone dysplasia
Codon, Nonsense
Fibrosis
Heredity
Heterozygote
Humans
Hypopituitarism
Hypopituitarism - genetics
Hypopituitarism - pathology
Lethality
Liver
Male
Membrane Proteins - genetics
Mutation, Missense
Nephronophthisis
Phenotype
Phenotypes
Retinitis
Retinitis pigmentosa
Retinitis Pigmentosa - genetics
Retinitis Pigmentosa - pathology
RNA Splicing
Skeleton
Splicing
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Summary:A rare syndrome was first described in 1997 in a 17-year-old male patient presenting with Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia (RHYNS). In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance. Up to now, the underlying genetic basis of RHYNS syndrome remains unknown. Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67. Sanger sequencing confirmed a paternally inherited nonsense c.622A > T, p.(Arg208*) and a maternally inherited missense variant c.1289A > G, p.(Asp430Gly), which perturbs the correct splicing of exon 13. Overall, TMEM67 showed one of the widest clinical continuum observed in ciliopathies ranging from early lethality to adults with liver fibrosis. Our findings extend the spectrum of phenotypes/syndromes resulting from biallelic TMEM67 variants to now eight distinguishable clinical conditions including RHYNS syndrome.
ISSN:1018-4813
1476-5438
DOI:10.1038/s41431-018-0183-6