Skeletal dysplasia

Gene: IFIH1

Green List (high evidence)

OI and decreasing bone density gp of SD - 3 cases with same R822Q variant. Also associated wth Aicardi-Goutieres syndrome type 7 - 615846; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Singleton-Merten syndrome 1 (182250)

Publications

• 25620204

Mode of pathogenicity
Other - please provide details in the comments

I don't know

Comment on list classification: 4 cases reported. All have the same gain of function variant. Genomics England clinicians confirm the phenotype is relevant.

Created: 21 Nov 2019, 12:31 a.m. | Last Modified: 21 Nov 2019, 12:31 a.m.

Panel Version: 1.226

Comment on mode of pathogenicity: A single variant, thought to act as a gain of function, has been identified.

Created: 21 Nov 2019, 12:29 a.m. | Last Modified: 21 Nov 2019, 12:29 a.m.

Panel Version: 1.223

Associated with Singleton-Merten syndrome 1 #182250 (AD) in OMIM with short stature and various skeletal abnormalities listed as clinical features.

PMID: 25620204 - Rutsch et al 2015 - identified the same missense mutation, c.2465G>A (p.Arg822Gln), in IFIH1 in Singleton-Merten syndrome (SMS) patients from two families and a simplex case. Functional studies suggest this is a a gain-of-function IFIH1 mutation. Patients showed early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis .

PMID: 28319323 - Pettersson et al 2018 - identified the same mutation c.2465G>A p.(Arg822Gln), in IFIH1in a mother and daughter with Singleton-Merten syndrome. Patient 1 presented with congenital glaucoma, spastic paraplegia, severe dental anomalies, kyphosis, osteoporosis, recurrent infections, muscle weakness, aortic insufficiency, pericarditis, short stature, and SLE. Her mother presented with milder dental anomalies and finger deformities.

Created: 21 Nov 2019, 12:14 a.m. | Last Modified: 21 Nov 2019, 12:28 a.m.

Panel Version: 1.221

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: IFIH1; Initial rating suggestion: green - codon R337 only

Created: 6 Mar 2019, 11:36 a.m.