Rare syndromic craniosynostosis or isolated multisuture synostosis

Gene: CHD7

Green List (high evidence)

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

Created: 5 Mar 2022, 6:18 p.m. | Last Modified: 5 Mar 2022, 6:18 p.m.

Panel Version: 2.65

Comment on list classification: Promoting this gene from grey to amber with a recommedation of green rating following GMS review. 3 cases reported with a craniosynostosis phenotype and supported model organism data, although incomplete penetrance is noted.

Created: 28 Jul 2021, 1:52 a.m. | Last Modified: 28 Jul 2021, 1:52 a.m.

Panel Version: 2.46

Associated with CHARGE syndrome #214800 (AD) in OMIM.

As reported by expert reviewer 3 cases reported with craniosynostosis and variants in CHD7 (PMID: 33844462 - De Luca et al 2021, PMID: 30498854 - Siakallis et al, 2019 and PMID: 33288889 - Tonne et al 2020). 2 had nonsense variants and the third had a duplication leading to a frameshift in CHD7. The variant reported by De Luca et al 2021 has also been reported previously in 4 individuals, but none of them have reported craniosynostosis indicating incomplete penetrance for this phenotype.

Model organism data supports the role of this gene in craniofacial development (PMID: 24975120 Sperry et al 2014 - mouse model and PMID: 22363697 Patten et al 2012 - zebra fish)

Created: 28 Jul 2021, 1:50 a.m. | Last Modified: 28 Jul 2021, 1:50 a.m.

Panel Version: 2.43

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

Phenotypes
CHARGE syndrome, OMIM:214800; CHARGE syndrome, MONDO:0008965

Publications

• 33844462
• 30498854
• 33288889
• 24975120
• 22363697

I don't know

Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053*) - NGS in proband, sanger sequencing used to exclude variant from the parents.
Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted.
In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected:
Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036*) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures.
Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis.

Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia.
Zebrafish model of CHARGE - flattening of the head is observed.
Sources: Expert Review

Created: 6 May 2021, 2:34 p.m. | Last Modified: 7 Jan 2022, 2:17 p.m.

Panel Version: 2.60

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
craniosynostosis

Publications

• 33844462
• 30498854
• 33288889