CRLS1

Inheritance Pattern: AR

Disease ID:MONDO:0859337

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0859337

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0859337

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *CRLS1* and *CRLS1*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 27, 2025. The *CRLS1* gene encodes cardiolipin synthase 1, an enzyme that catalyzes the synthesis of cardiolipin (CL) by specifically transferring a phosphatidyl group from CDP-diacylglycerol to phosphatidylglycerol. The *CRLS1* gene was first reported in relation to autosomal recessive *CRLS1*-related primary mitochondrial disease in 2022 (PMID: 35147173). *CRLS1* has been associated with a single disease entity to date; combined oxidative phosphorylation deficiency 57 [OMIM# 620167]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *CRLS1*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three missense variants identified in four unrelated cases from two publications (PMIDs: 35147173, 39417332). At least two cases were more severely affected and had non-immune hydrops fetalis and bilateral pleural effusions at birth, hypertrophic cardiomyopathy, epileptic encephalopathy, and progressive neurologic deterioration with death in the first year of life. Additional features seen in reported cases include global developmental delay, slowly progressive encephalopathy, sensorineural hearing loss, seizures, and bull’s eye maculopathy. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), functional alterations in non-patient cells (PMID: 35147173), and mouse models (PMIDs: 38556544, 31914590). In summary, there is moderate evidence to support the relationship between *CRLS1* and autosomal recessive *CRLS1*-related primary mitochondrial disease. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 27, 2025 (SOP Version 11).