Paediatric disorders - additional genes

Gene: SPRTN

Green List (high evidence)

Comment on list classification: There are 3 individuals from 2 unrelated families reported in literature with biallelic LoF variants in SPRTN and Ruijs-Aalfs syndrome. Individuals presented with early onset hepatocellular carcinoma, genomic instability, and progeroid features (PMID: 25261934). Sprtn-deficiency in mice recapitulated the human phenotype, except for carcinoma susceptibility (PMID: 25501849). Based on the available evidence, this gene should be promoted to Green on Paediatric disorders - additional genes at the next GMS update

Created: 13 Nov 2025, 5:09 p.m. | Last Modified: 13 Nov 2025, 5:12 p.m.

Panel Version: 7.24

PMID: 25261934 Lessel et al., 2014
Reported biallelic germline mutations in SPRTN in three patients from two unrelated families, affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. Seq method: linkage analysis + WES.

Family A: NM_032018.7:c.723del, p.Lys241Asnfs*9 homozygous
Family A originally described in PMID: 12503110 Ruijs et al., 2003 - Report of a Moroccan boy from a consanguineous family with chromosomal breakage syndrome, who died at 17yo due to hepatocellular carcinoma. Presented with short stature, bilateral cataracts, premature hair graying.

Family B: NM_032018.7:c.350A>G, p.Tyr117Cys & c.717_718+2delAGGT compound heterozygous
Family B = nonconsanguineous Australian family of European ancestry. 2 affected male sibs B-II:1 and B-II:4 presented with low body weight, micrognathia, triangular face, muscular atrophy, lipodystrophy, bilateral simian creases, delayed bone age and mild joint restrictions. Both individuals developed early onset HCC at age 16 and 14.

FUNCTIONAL EVIDENCE: PMID: 25501849: Maskey et al., 2014: Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes. Complete Spartan knockout causes early embryonic lethality; hypomorphic mice are viable, but growth retarded and develop cataracts, lordokyphosis and cachexia at a young age. Mouse model recapitulated human phenotype, except for the carcinoma susceptibility (no tumours detected in 1 year old Spartan-deficient mice).

SPRTN is associated with AR Ruijs-Aalfs syndrome, OMIM:616200 (OMIM accessed 13th Nov 2025).

Created: 13 Nov 2025, 5 p.m. | Last Modified: 13 Nov 2025, 5:10 p.m.

Panel Version: 7.24

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Ruijs-Aalfs syndrome, OMIM:616200; progeroid features-hepatocellular carcinoma predisposition syndrome, MONDO:0014527

Publications

• 12503110
• 25261934
• 25501849

Green List (high evidence)

2 families in literature with progeroid phenotype and susceptibility to hepatocellular carcinoma.
DNA repair defects (chromosome breakage observed) in affected patients - PMID:25261934

1 family in NWGLH - IUGR & IGF abnormalities referral. Subsequently reported with hepatocellular carcinoma and described as progeroid - remarkably consistent phenotype with families in literature. Chromosome breakage studies being arranged.
(100KGP - https://cva.genomicsengland.nhs.uk/case/25972-1 - homozygous final exon nonsense/truncating variant)

3rd family = sufficient for green rating?
Sources: Literature, NHS GMS

Created: 30 Oct 2025, 4:54 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Ruijs-Aalfs syndrome, MIM# 616200

Publications

• 12503110
• 25261934