GJC2 was first reported in relation to an autosomal recessive hypomyelinating leukodystrophy 2 (HLD2) in 2004 (Uhlenberg et al., PMID: 15192806). Originally, this condition was described as Pelizaeus Merzbacher-like disease given the very similar phenotypic presentation. GJC2 was also reported in association with autosomal recessive spastic paraplegia 44 (SPG44) in 2009 (Orthmann-Murphy et al., PMID 19056803). In this paper, the authors reported a milder phenotype consisting of a later-onset, slowly progressive, complicated spastic paraplegia with hypomyelinating leukoencephalopathy. Additionally, GJC2 was reported in association with autosomal dominant lymphatic malformation 3 (LMPHM3) in 2010 (Ferrekk et al., PMID 20537300). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found that a phenotypic spectrum exists and no difference in molecular mechanism (loss-of-function) or inheritance pattern (autosomal recessive) between HLD2 and SPG44; therefore these two disease entities have been lumped into the HLD2 disease entity (OMIM:608804, MONDO:0012125). However, we did find a difference in molecular mechanism, inheritance pattern, and phenotype between HLD2 and LMPHM3. The latter disease entity has been split to be curated separately. Nine variants (missense, nonsense, and frameshift) that have been reported in seven probands across six publications (PMIDs: 16707726, 31270756, 26354221,15192806, 19056803, 34840390) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by experimental evidence, including a mouse model (PMID:12805295). In summary, there is definitive evidence supporting the relationship between GJC2 and autosomal recessive hypomyelinating leukodystrophy 2, also known as GLC2-related hypomyelinating leukodystrophy. 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 Leukodystrophy GCEP on January 27, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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