PYCR2

Inheritance Pattern: AR

Disease ID:MONDO:0014632

Submitter: Illumina

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0014632

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0014632

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014632

Submitter: ClinGen

*PYCR2* was first reported in association with autosomal recessive hypomyelinating leukodystrophy 10 in 2015 (Nakayama T et al., PMID: 25865492). The characteristic clinical presentation of affected individuals includes failure to thrive, microcephaly, craniofacial dysmorphism, progressive psychomotor disability, hyperkinetic movements, and axial hypotonia with variable appendicular spasticity. Brain magnetic resonance imaging demonstrated global brain atrophy and white matter T2 hyperintensities (PMID: 34037307; PMID: 3714174). More recent reports have asserted that variants in the *PYCR2* gene may also be associated with a late childhood to adult-onset hereditary spastic paraplegia (PMID 32920934 ; PMID: 37141741) phenotype. The individuals reported presented primarily with lower limb spasticity and gait difficulty. While brain imaging appreciated some changes and atrophy, there was no clear hypomyelination observed. However, there appears to be enough phenotypic overlap to consider a possible spectrum of presentation, with HSP being on the milder end. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the single disease entity has been maintained: hypomyelinating leukodystrophy 10 (OMIM: 616420). Multiple pathogenic variants, including missense, splice-site, and nonsense variants, have been reported in numerous probands across several publications (PMID: 27130255; PMID: 32330411; PMID: 27860360; PMID: 33771508) and are included in this curation. Although additional evidence exists in the literature, the maximum score for genetic evidence (12 points) has already been reached. The proposed disease mechanism is loss of function, with functionally tested missense variants demonstrating reduced enzymatic activity relative to the wild-type protein. While these variants were reported in patients with HLD10, the seven cases of HSP were found to harbor two unique homozygous missense variants (M195T and V128A). These late childhood to adult-onset hereditary spastic paraplegia cases were not included in the overall genetic evidence scoring, as the maximum score had already been reached and functional studies were not available for these variants, despite their location amongst other variants reported in patients with HLD10. Notably, the M195T and V128A variants have not been reported in individuals with HLD10 to date. Functional studies further support the gene–disease relationship. *Pycr2 *knockout mouse models phenocopied the human disorder, including microcephaly and hypomyelination. Neurochemical studies demonstrated elevated cerebral glycine levels in both mutant mice and affected individuals (PMID: 33734376). Five of the seven individuals reported with the HSP phenotype also exhibited cerebral glycine peaks on MRS (PMID: 3714174). Additional mechanistic studies linked *PYCR2* deficiency to upregulation of SHMT2, resulting in increased glycine levels that may contribute to neurotoxicity and the leukodystrophy phenotype. SHMT2 knockdown partially rescued neurite defects and axonal beading in *Pycr2* knockout neurons (PMID: 32330411). Furthermore, morpholino-based knockdown of the zebrafish *PYCR2* ortholog, *pycr1b*, recapitulated the human microcephaly phenotype. This phenotype was rescued by wild-type human PYCR2 mRNA, but not by mutant mRNAs, further supporting the pathogenicity of the identified variants (PMID: 25865492). In summary, there is definitive evidence supporting the relationship between *PYCR2 *and autosomal recessive hypomyelinating leukodystrophy 10, also known as *PYCR2*-related hypomyelinating leukodystrophy, and potentially a broader phenotypic spectrum including a hereditary spastic paraplegia phenotype. This association has been repeatedly demonstrated in both research and clinical diagnostic settings and has been consistently upheld over time. This classification was approved by the ClinGen IEM GCEP at the meeting on May 22, 2026. The Leukodystrophy and Leukoencephalpathy GCEP also contributed to this curation. (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0014632

Submitter: Labcorp Genetics (formerly Invitae)