Rare syndromic craniosynostosis or isolated multisuture synostosis

Gene: NFIA

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 4:25 p.m. | Last Modified: 1 Feb 2023, 4:25 p.m.

Panel Version: 3.3

Green List (high evidence)

15 year old boy with healthy non-consanguineous parents and two heathy sibs. Metopic synostosis treated at 2 months. At age of 2 years he developed hydrocephalus, thin corpus callosum, mild developmental delay, autism, macrocephaly, supernumerary teeth and reduced vision. Facail features included a long face, hypertelorism, short nose, long philtrum, micrognathia and simple low-set ears.

WES (trio): Two de novo variants were idenitifed in cis c.124A>T p.(Lys42*) and c.250C>T p.(Arg84*). Not reported in gnomAD and are expected individually to result in degredation of NFIA mRNA due to nonsense mediated decay. The c.124A>T variant is considered to be the causal variant as they are in cis . NFIA has a high probability of LOF intolerence (pLi = 1).

They categorise as PVS1, PS2, PM2 - pathogenic

Het pathogenic LOF variants associated with brain malformations with or without urinary tract defects. Craniosynostosis has been reported in one single case and in 1 family with 3 out of 4 affected individuals all assoc with microdeleteions involving NFIA alone - Nyboe et al 2015 and Rao et al 2014 - descrbed in previous gene review.

Yoon et al, 2019: Molecular diagnosis of crasniosynostosis using targeted NGS: custom panel of 34 CRS genes enrolled 110 Korean patients with CRS (40 syndromic, 70 non-syndromic) - deletion of 7765kb including this entire gene - craniosynostosis in chromosome 1p32-p31 deletion syndrome.

Tonne et al 2021, 381 children with craniosynostosis - 104 syndromic cases. Table 2 chromosome aberrations in individuals with syndromic CS - del 1p32.3p31.2, g.53675707_66644963del- 13Mb del including the NFIA gene.

5 unrelated cases of syndromic craniosynostosis in assocation with the NFIA gene - reclassify as green.

Created: 27 Jan 2022, 9:59 a.m. | Last Modified: 27 Jan 2022, 9:59 a.m.

Panel Version: 2.61

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Metopic synostosis, hydrocephalus, thin corpus callosum, mild developmental delay, autism, macrocephaly

Publications

• 35080095
• 31754721
• 33288889

I don't know

One patient with developmental delay, macrocephaly, hypoplastic corpus callosum, metopic synostosis, and hematuria has been described with an intragenic microdeletion of exons 49 of NFIA [Rao et al., 2014]. Additionally, a family (a father and 3 children) had a 109-kb deletion of chromosome 1p31.3 (deleting exons 1 and 2 of NFIA ) [Nyboe et al., 2015]. Their phenotype comprised sagittal or lambdoid suture synostosis, macrocephaly, developmental delay and mild mental retardation, overgrowth, bilateral proximally placed first fingers, and low-set ears [Nyboe et al., 2015].; Review on behalf of Tracy Lester and Andrew Wilkie

Created: 11 Apr 2019, 8:40 a.m.

I don't know

Comment on list classification: As Expert reviewer notes, there are sufficient cases reported with a craniosynostosis phenotype and variants in this gene to promote it to green following GMS review.

Created: 13 Apr 2022, 3:46 p.m. | Last Modified: 13 Apr 2022, 3:46 p.m.

Panel Version: 2.73

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: NFIA; Suggested initial gene rating: amber

Created: 11 Apr 2019, 8:37 a.m.