Rare syndromic craniosynostosis or isolated multisuture synostosis

Gene: NFIX

Green List (high evidence)

Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there is sufficient evidence (4 unrelated cases) available for promotion of this gene to GREEN rating in the next GMS update.

Created: 11 May 2023, 10:10 a.m. | Last Modified: 11 May 2023, 10:10 a.m.

Panel Version: 4.44

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Malan syndrome, OMIM:614753; Marshall-Smith syndrome, OMIM:602535; craniosynostosis, MONDO:0015469

Publications

• 33288889
• 35997807

Green List (high evidence)

• In a patient with lambdoid and bicoronal craniosynostosis, a de novo variant encoding p.(Arg121Cys) was identified in NFIX (Timberlake et al., 2023).
• A child with metopic craniosynostosis was shown to harbour a variant within the DNA-binding domain of NFIX (p.(Arg116Trp)) (Timberlake et al., 2023).
• A de novo microdeletion within NFIX ((c.(818+1_819-1)_(1078+1_1079-1)), deleting exons 6–7 and resulting in a predicted p.(Ser273Argfs*63) frameshift variant, was identified via microarray in a child with syndromic sagittal and coronal craniosynostosis (Timberlake et al., 2023).
• A child with syndromic sagittal craniosynostosis was shown to have a de novo missense variant within the nuclear localisation sequence of NFIX (p.(Met48Lys)) (Tønne et al., 2021).

Four families with variants in NFIX – all absent from gnomAD. Only variant not affecting a functional domain is p.(Met48Lys) which is reported in ClinVar as likely pathogenic for Malan overgrowth syndrome.

Created: 2 Mar 2023, 1:32 p.m. | Last Modified: 2 Mar 2023, 1:32 p.m.

Panel Version: 3.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

I don't know

Cases with CSS in Shaw Am J Med Genet (2010) and Ittleman Am J Med Genet (2018),AW aware of one unpublished case and there are earlier clinical cases in literature. Specific mutations in NFIX cause Marshall-Smith, see Schanze Hum Mutat 14. Added by GOSH - Shaw et al (2010) reported Craniosynostosis in 5/38 (13%) of patients with MarshallSmith syndrome but no molecular confirmation. Ittleman et al (2018) reported patient with MarshallSmith syndrome BUT NFIX gene could not be conducted. ; Review on behalf of Tracy Lester/Andrew Wilkie/GOSH

Created: 5 Mar 2019, 11:33 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Marshall-Smith syndrome

Green List (high evidence)

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

Created: 11 Oct 2023, 11:55 a.m. | Last Modified: 11 Oct 2023, 11:55 a.m.

Panel Version: 4.174

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: NFIX; Suggested initial gene rating: amber

Created: 5 Mar 2019, 11:21 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted