Submission Details

PCYT1A was first reported in relation to autosomal recessive spondylometaphyseal dysplasia with cone-rod dystrophy in 2014 (Hoover-Fong et al., PMID: 24387990; Yamamoto et al., PMID: 24387991 ). Spondylometaphyseal dysplasia with cone-rod dystrophy (SMDCRD) is characterized by postnatal growth deficiency resulting in profound short stature, rhizomelia with bowing of the lower extremities, platyspondyly with anterior vertebral protrusions, progressive metaphyseal irregularity and cupping with shortened tubular bones, and early-onset progressive visual impairment associated with a pigmentary maculopathy and electroretinographic evidence of cone-rod dysfunction. Later, Testa et al reported biallelic PCYT1A variants in three young patients from two different Italian families with isolated retinal dystrophy (PMID: 28272537). At least 11 variants (variant types including missense, nonsense and frameshift) that have been reported in 10 probands in 3 publications (PMIDs: 24387990, 24387991, 28272537) are included in this curation. These variants have been demonstrated to segregate in compound heterozygous or homozygous state in the affected individuals. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease association is supported by in-vivo studies in drosophila, in which siRNA-mediated knockdown of PCYT1A led to blindness in drosophila (PMID: 29754800). Immunostaining of endogenous PCYT1A also demonstrated its expression in mouse retina tissue (PMID: 29754800). In summary, PCYT1A is strongly associated with autosomal recessive spondylometaphyseal dysplasia with cone-rod dystrophy. Three patients with nonsyndromic retinal dystrophy and compound heterozygous PCYT1A variants (truncating variant + missense) have also been reported.