Rare syndromic craniosynostosis or isolated multisuture synostosis

Gene: ADAMTSL4

Green List (high evidence)

Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN at the next GMS update.

Created: 5 May 2023, 8:25 p.m. | Last Modified: 5 May 2023, 8:25 p.m.

Panel Version: 4.5

PMID:20702823 reported 10 affected individuals from five unrelated Norwegian families with homozygous variants (c.767_786del/ p.Gln256Profs∗38) and they presented with ectopia lentis et pupillae. All these patients were surgically corrected for craniosynostosis.

PMID:22871183 reported a patient with right coronal synostosis and bilateral ectopia lentis, who harboured the same homozygous deletion variant. The proband's mother, father and one sibling are heterozygous carriers of the variant.

PMID:28642162 reported a Dutch family with monozygotic twins harbouring compound heterozygous variants (c.767_786del/ p.Gln256Profs∗38 & c.2254C > T/ p.Gln752∗) and both presented with craniosynostosis and ectopia lentis.

PMID:35378950 reported two unrelated families with craniosynostosis and ectopia lentis. Family 1’s proband is compound heterozygous (c.767_786del & c.2177 + 3_2177 + ) and family 2 has two homozygous affected siblings with c.767_786del, however the older sister did not have craniosynostosis (ectopia lentis only).

Created: 5 May 2023, 8:20 p.m. | Last Modified: 5 May 2023, 8:21 p.m.

Panel Version: 4.1

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
craniosynostosis with ectopia lentis, MONDO:0011347

Publications

• 10215540
• 20702823
• 22871183
• 28642162
• 35378950

Green List (high evidence)

• One patient with right coronal synostosis and bilateral ectopia lentis has been shown to harbour a homozygous deletion in exon 6 of ADAMTSL4 (c.767_786del), encoding a premature termination codon, p.(Gln256Profs*38). The proband's mother, father and one sibling are heterozygous carriers of the variant (Chandra et al., 2013).
• Two reported cases of craniosynostosis with ectopia lentis, each harbouring recessive variants in ADAMTSL4. The first patient presented with bilateral coronal craniosynostosis, retrusion of the frontal bones, moderate retrusion of the surpraorbital rims, anteroposterior enlargement of the anterior fontanelle with moderate supraorbital rim retrusion, and mild proptosis associated with a heterozygous 20 base pair deletion (c.767_786del; p.(Gln256Profs*38)) and a splice site frameshift deletion (c.2177+3_2177+6delGAGT; p.(?)) (confirmed to be in trans by dideoxy-sequencing). The second patient was diagnosed with sagittal craniosynostosis at five months of age by CT scan and was treated with a cranioplasty at six months of age. A homozygous 20 bp deletion in ADAMTSL4 (c.767_786del, p.(Gln256Profs*38)) was identified in the patient and his sister (Gustafson et al., 2022).
• A further 12 cases have been previously reported of craniosynostosis and recessive variants in ADAMTSL4 (Gustafson et al., 2022).

Created: 2 Mar 2023, 1:16 p.m. | Last Modified: 2 Mar 2023, 1:16 p.m.

Panel Version: 3.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

I don't know

2 published cases with CSS as documented in Twigg&Wilkie AJHG 15 ; Review on behalf of Tracy Lester and Andrew Wilkie

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

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Ectopia lentis -225200/225100

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: ADAMTSL4; Suggested initial gene rating: amber

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

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Red List (low evidence)

craniosynostosis described in single case report

Created: 14 Sep 2015, 12:35 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
ectopia lentis

Publications

• 22871183
• 20702823