Stickler syndrome

Gene: BMP4

Green List (high evidence)

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

Created: 30 Jan 2023, 3:54 p.m. | Last Modified: 30 Jan 2023, 3:54 p.m.

Panel Version: 3.3

Comment on list classification: Although there is not 3 cases reported of patients with Stickler syndrome and variants in this gene, there is evidence of association with an eye phenotype. This gene has been reviewed as green by an Stickler syndrome expert. Therefore it is recommended for a green rating following GMS review.

Created: 9 Sep 2022, 6:23 p.m. | Last Modified: 9 Sep 2022, 6:23 p.m.

Panel Version: 2.35

Associated with Microphthalmia, syndromic 6, #607932 and Orofacial cleft 11, #600625 in OMIM.

As expert reviewer notes there is one 3 generation family published with affected members with a diagnosis of Stickler syndrome in which a heterozygous variant in BMP4 that results in a premature stop codon was identified and found to segregate with the disease: NM_001202.3: c.130G>T, p.(Gly44Ter) (PMID:30568244 - Nixon et al 2019).

Other evidence for the role of this gene in eye disease:
PMID:35022715 - Guggenheim et al 2022 - performed a genome-wide association study for refractive error in 51 624 unrelated adults, of European ancestry. 10 individuals with a rare (MAF = 0.0002) intronic variant in BMP4 (14:53951768:C:T) had a refractive error that was −0.74 D more myopic, on average, than non-carriers.

PMID:34926457 - Jiang et al 2021 - screened 7000+ probands with ocular phenotypes and identified 8 patients from 4 Chinese families with BMP4 truncation mutations and pathologic myopia.

Created: 9 Sep 2022, 6:17 p.m. | Last Modified: 9 Sep 2022, 6:17 p.m.

Panel Version: 2.32

Green List (high evidence)

There is published evidence of this gene causing an AD variant of Stickler syndrome in a 3 generation family in a Mendelian pattern of causation appropriate for reporting in a diagnostic setting.
Significant published evidence associating BMP4 with myopia, refractive error, midline cleft and connective tissue disruption all of which are associated features of the Stickler syndromes (see above)
No convincing evidence exists or has emerged that contradicts the role of the gene in Stickler syndrome.

Created: 22 Aug 2022, 9:27 a.m. | Last Modified: 22 Aug 2022, 9:27 a.m.

Panel Version: 2.27

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
AD Stickler syndrome

Publications

• 35979589
• 30568244
• 35022715
• 34926457

Comment on publications: Added publication and removed PMID: 25663169; 30362103, which were for LOXL3 and not BMP4

Created: 15 Jun 2021, 2:53 p.m. | Last Modified: 15 Jun 2021, 2:53 p.m.

Panel Version: 2.22

I don't know

Included in the review:
https://doi.org/10.1177/2633004020978661

Phenotype in certain cases resembles Stickler syndrome, including facial dysmorphic features, hearing loss, and cleft palate. One extended family with clinically diagnosed Stickler syndrome reported:PMID: 30568244.

Created: 10 Jun 2021, 11:05 a.m. | Last Modified: 10 Jun 2021, 11:05 a.m.

Panel Version: 2.16

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Microphthalmia; Micrognathia; Retrognathia; Midface hypoplasia; Cleft palate; hearing loss

Publications

• PMID: 30568244

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Submitted by Alan Richards on behalf of East Mids & East of England Genomic Laboratory Hub.
Sources: Expert list

Created: 5 Apr 2019, 4:41 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 25663169
• 30362103