Rare syndromic craniosynostosis or isolated multisuture synostosis
Gene: PJA1Expert reviewer (Helen Lord) confirms amber rating.Created: 26 Jan 2021, 5:23 p.m. | Last Modified: 26 Jan 2021, 5:23 p.m.
Panel Version: 2.23
HGMD - reported by Suzuki et al, 2020 PMID32530565: exome seq of 95 patients with neurodevelopmental disorders incl 51 with trigonocephly. A hemizygous PJA1 variant was found recurrently in 7 male Japanese NDD patients from 5 families, 3 famiies (5 individuals) had trigonocephaly, all were inherited from unaffected mothers. Not detected in 886 Japanese control variants, Pja1 knock in mice carrying p.Arg365Cys (equiv of Arg376Cys) in humans, showed a significant decrease in PJA1 protein amount, suggesting LOF effect of the variant. Rating as Amber - need further cases to classify further.Created: 22 Jan 2021, 10:44 a.m. | Last Modified: 22 Jan 2021, 10:44 a.m.
Panel Version: 2.19
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
Neurodevelopmental disorders; trigonocephaly
Publications
Comment on list classification: Rating Amber based on evidence provided in a single publication (PMID:32530565). Additional case supporting pathogenicity of other PJA1 variants required prior to inclusion on a diagnostic panel.Created: 19 Nov 2020, 4:11 p.m. | Last Modified: 19 Nov 2020, 4:11 p.m.
Panel Version: 2.14
Recurrent variant, p.Arg376Cys, reported in 7 Japanese individuals from 5 independent families, of which 5 patients were diagnosed with mild trigonocephaly. Some supportive data in a mouse model. Individuals shared a common haplotype, suggestive of founder effect.
Sources: Expert listCreated: 19 Nov 2020, 4:09 p.m.
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
Trigonocephaly; Intellectual disability
Publications
Phenotypes for gene: PJA1 were changed from Trigonocephaly; Intellectual disability to Trigonocephaly; Intellectual disability; Neurodevelopmental disorders
Gene: pja1 has been classified as Amber List (Moderate Evidence).
Gene: pja1 has been classified as Red List (Low Evidence).
gene: PJA1 was added gene: PJA1 was added to Craniosynostosis. Sources: Expert list founder-effect tags were added to gene: PJA1. Mode of inheritance for gene: PJA1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: PJA1 were set to 32530565 Phenotypes for gene: PJA1 were set to Trigonocephaly; Intellectual disability