Rare syndromic craniosynostosis or isolated multisuture synostosis

Gene: LTBP1

Green List (high evidence)

Pottie et al, 2021 - 8 affected individuals: 6/8 have craniosynostosis affecting the coronal, sagittal and lambdoid sutures in 4 unrelated families. in all families were hom truncating variants - all variants segregate in family members accoding to disease and carrier status (parental testing undertaken).
Some functional work undertaken - in vitro studies suggest different LTBP1-truncating variants have disctinct molecular signatures on ECM development and TGFB signalling.
zebrafish in vivo studies - note no craniofacial abnormalities nor cranioaynoatsis observed - thought to be explained by induction of genetic compensation mechanisms, partially rescuing the craniosynostosis phenotype.

Created: 7 Jan 2022, 3:30 p.m. | Last Modified: 7 Jan 2022, 3:30 p.m.

Panel Version: 2.60

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 33991472

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

Helen Lord's review concurs with the recommendation to rate this gene green.

Created: 12 Jan 2022, 12:07 p.m. | Last Modified: 12 Jan 2022, 12:07 p.m.

Panel Version: 2.61

Comment on list classification: Promoting from grey to amber but with a recommendation for green rating following GMS review. 4 cases reported with craniosynostosis in 6/8 individuals

Created: 28 Jul 2021, 2:22 a.m. | Last Modified: 28 Jul 2021, 2:22 a.m.

Panel Version: 2.48

Associated with Cutis laxa, autosomal recessive, type IIE #619451 (AR) in OMIM.

PMID: 33991472 - Pottie et al 2021 - report 8 individuals from 4 unrelated consanguineous families with 4 different homozygous premature truncating LTBP1 variants. Core clinical features include cutis laxa, craniosynostosis, a copper beaten calvarium, short stature, and discernible craniofacial characteristics. Craniosynostosis reported in 6/8 individuals from 4 families.

Created: 28 Jul 2021, 2:19 a.m. | Last Modified: 28 Jul 2021, 2:19 a.m.

Panel Version: 2.46

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cutis laxa, autosomal recessive, type IIE, OMIM:619451; craniosynostosis, MONDO:0015469

Publications

• 33991472

Green List (high evidence)

PMID:33991472
- Premature truncating variants in multiple affected individuals from 4 unrelated consanguineous families.
- Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly).
- Functional studies done on patient fibroblasts and zebrafish models.
Sources: Literature

Created: 12 Jun 2021, 3:12 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Craniosynostosis; cutis laxa; intelectual disability

Publications

• 33991472