White matter disorders and cerebral calcification - childhood onset

Gene: CNP

Green List (high evidence)

Comment on list classification: There are two unrelated families and functional evidence including mouse model in support of the association of CNP with leukodystrophy. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 3 Sep 2026, 7:32 p.m. | Last Modified: 3 Sep 2026, 7:32 p.m.

Panel Version: 8.13

PMID:32128616 (2020) reported a consanguineous Omani family with three affected siblings displaying a remarkably consistent phenotype of neuroregression with profound brain white matter loss. They were identified with a homozygous missense variant c.245C>T (p.Ser82Leu) in CNP gene, suggested to function as a null allele (immunoblot + F-actin defects in fibroblasts).

PMID:40396300 (2025) reported a novel case of a child presenting with hypomyelinating leukodystrophy type 20, and identified with homozygous nonsense variant c.295G>T (p.Glu99Ter), supported by RT-qPCR showing reduced CNP mRNA.

PMID:12590258 (2003) reported that deficiency of CNP in mice led to axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death.

This gene has been tentatively associated with hypomyelinating leukodystrophy in OMIM (MIM #619071 - last accessed 03 September 2026), but not in Gene2Phenotype or ClinGen.

Created: 3 Sep 2026, 7:27 p.m. | Last Modified: 3 Sep 2026, 7:28 p.m.

Panel Version: 8.10

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Leukodystrophy, hypomyelinating, 20, OMIM:619071; leukodystrophy, hypomyelinating, 20, MONDO:0033657

Publications

• 12590258
• 32128616
• 40396300

Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.

Created: 2 Jun 2021, 1 p.m. | Last Modified: 2 Jun 2021, 1 p.m.

Panel Version: 1.134

I don't know

Single consanguineous family described with homozygous missense in affected child (additional two affected deceased offspring unavailable for testing; healthy carrier parents and sibling).
Loss of protein by Western blot and defect in F-actin structure and organization observed in patient fibroblasts.
Deficiency of CNP in mouse has previously been shown to cause a lethal white matter neurodegenerative phenotype (PMID: 12590258), similar to the phenotype observed in this family.
Sources: Literature

Created: 3 Jun 2020, 10:55 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hypomyelinating leukodystrophy

Publications

• 32128616
• 12590258