SRD5A3

Inheritance Pattern: AR

Disease ID:MONDO:0012885

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012885

Submitter: ClinGen

SRD5A3 was first reported in relation to the autosomal recessive disorder, SRD5A3-congenital disorder of glycosylation (SRD5A3-CDG), in 2010 (Cantagrel et al, PMID: 20637498; Morava et al, PMID: 20852264). SRD5A3-CDG is characterized by eye abnormalities (including coloboma and cataracts), developmental delay and intellectual disability, neurological symptoms, skin disorders, and curvature of the spine. Most patients have an abnormal type I pattern on serum transferrin glycosylation analysis (Jaeken et al, 2020, PMID: 32424323). Based on the ClinGen Lumping and Splitting guidelines, two disorders - congenital disorder of glycosylation, type 1q (CDG 1q) (MIM# 612379), and Kahrizi syndrome (MIM# 612713) - will be lumped as "SRD5A3-congenital disorder of glycosylation". Kahrizi syndrome was first reported in 2009 (Kahrizi et al, PMID: 18781183) when the gene was linked to a region on chromosome 4 in an Iranian family. The following year, Cantagrel et al reported biallelic loss of function variants in SRD5A3 in patients with CDG1q. Those patients had symptoms overlapping with Kahrizi syndrome in addition to evidence of reduced N-glycosylation (Cantagrel et al, PMID: 20637498). In 2011, a homozygous frameshift variant was reported in the family with Kahrizi syndrome (Kahrizi et al, PMID: 20700148). Based on those reports, and more recently reported cases, the molecular mechanism is loss of function and the inheritance pattern in autosomal recessive. The condition is now known as SRD5A3-CDG. At least 38 patients from 26 families have been reported in the literature (Jaeken et al, 2020, PMID: 32424323). Ten variants (nonsense, frameshift, intronic, missense) that have been reported in 10 probands in 4 publications were included in this curation (Cantagrel et al, 2010, PMID: 20637498; Kahrizi et al, 2011, PMID: 20700148; Wheeler et al, 2016, PMID: 27480077; Kamarus Jaman et al, 2021, PMID: 34925443). In addition, segregation evidence was included from two Iranian families, each segregating a different SRD5A3 variant (Cantagrel et al, 2010, PMID: 20637498; Kahrizi et al, 2011, PMID: 20700148). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by the biochemical function of the gene product, which is involved in reduction of polyprenol to dolichol, an essential step in N-glycosylation (Cantagrel et al, 2010, PMID: 20637498; Stiles and Russell, 2010, PMID: 20655462), rescue of N-glycosylation by the human gene in a yeast mutant (Cantagrel et al, 2010, PMID: 20637498), and the findings in mouse models including a conditional null cerebellar mouse knock out (Cantagrel et al, 2010, PMID: 20637498; Medina-Cano et al, 2018, PMID: 30311906). In summary, there is definitive evidence supporting the relationship between SRD5A3 and SRD5A3-congenital disorder of glycosylation, an autosomal recessive condition. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on January 17, 2024 (SOP v10).

Inheritance Pattern: AR

Disease ID:MONDO:0012885

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0012885

Submitter: Labcorp Genetics (formerly Invitae)