Retinal disorders

Gene: CYP2U1

Green List (high evidence)

Comment on list classification: As reviewed by Cassandra Smith, individuals with biallelic variants in CYP2U1 may present with retinal abnormalities, which fits into the scope of this panel - there at least 8 unrelated individuals reported in literature. The retinal disease has a variable age of onset (ranging from 6 to 32 years old in reported cases), sometimes appearing as the first symptom, before spasticity. Based on the available evidence, CYP2U1 should be rated Green for Retinal disorders.

Created: 17 Sep 2025, 3:28 p.m. | Last Modified: 17 Sep 2025, 3:28 p.m.

Panel Version: 8.25

CYP2U1 is known to cause hereditary spastic paraplegia, with a variable spectrum of other symptoms being reported: intellectual disability, dystonia, pseudoxanthoma elasticum, and visual impairments (pigmentary degenerative maculopathy, loss of visual acuity, photophobia). There are at least 8 unrelated individuals with retinal abnormalities with biallelic variants in CYP2U1, harbouring missense, stop-gained, splice-altering, and frameshift variants (PMID: 23176821, 26914923, 33107650, 34828401, 38058766, 39605873). The retinal disease has a variable age of onset (ranging from 6 to 32 years old in reported cases) – sometimes appearing as the first symptom, before spasticity (e.g. PMID:26914923, 39605873).

FUNCTIONAL EVIDENCE: A Cyp2u1−/− mouse model recapitulated the retinal impairments observed in patients – mice exhibited a late-onset (18 mo) ophthalmologic phenotype characterized by a cone dystrophy (PMID: 34546337 Pujol et al., 2021). Skin fibroblasts of an individual with c.61_73del, p.(Leu21Trpfs∗19) in CYP2U1 showed reduced oxygen consumption compared to controls, as well as structural abnormalities of the mitochondrial membrane (PMID: 23176821 Tesson et al., 2012). Expressing CYP2U1 with missense variants in HEK293T cells demonstrated that most missense variants were functionally inactive, due to loss of proper heme binding or destabilization of the protein structure (PMID: 29034544 Durand et al., 2018). Thus, the proposed disease mechanism is LoF leading to mitochondrial dysfunction - a common driver for degenerative retinal disease. Based on the available evidence, CYP2U1 should be rated Green for Retinal disorders.

The gene is associated with Spastic paraplegia 56, autosomal recessive (OMIM:615030, accessed 17th Sep 2025). It is also Definitive for CYP2U1-related spastic paraplegia in G2P (G2P00349).

Created: 17 Sep 2025, 3:25 p.m. | Last Modified: 17 Sep 2025, 3:25 p.m.

Panel Version: 8.25

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 56, autosomal recessive, OMIM:615030; retinal disorder, MONDO:0005283

Publications

• 23176821
• 26914923
• 29034544
• 33107650
• 34546337
• 34828401
• 38058766
• 39605873

Green List (high evidence)

In some families, it appears visual symptoms may present before spasticity/neurological phenotype.

PMID: 26914923 - Three patients from one family, where visual issues (pigmentary degenerative maculopathy) presented before spasticity. Biallelic loss of function variant identified

PMID: 34828401 - Patient presenting with bilateral progressive visual loss and photophobia. Biallelic loss of function variant identified

PMID: 39605873 - Two sibs with compound heterozygous variants. One had manifest neurological abnormalities since early childhood; the second had no neurological abnormalities. Both had opthalmological abnormalities
Sources: Literature

Created: 19 May 2025, 9:14 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• PMID: 26914923
• 34828401
• 39605873