Childhood onset hereditary spastic paraplegia

Gene: ARL6IP1

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

Created: 14 Mar 2022, 1:30 p.m. | Last Modified: 14 Mar 2022, 1:30 p.m.

Panel Version: 2.130

Green List (high evidence)

Comment on list classification: Leaving rating as amber but with recommendation for promotion to green at the next review. 4 cases reported with 3 different variants.

Created: 30 Jun 2021, 2:25 p.m. | Last Modified: 30 Jun 2021, 2:25 p.m.

Panel Version: 2.42

Provisionally associated with ?Spastic paraplegia 61, autosomal recessive #615685 in OMIM. (AR)

PMID: 24482476 - Novarino et al 2014 - analyzed 55 families displaying autosomal recessive-Hereditary spastic paraplegia by whole-exome sequencing. Found a homozygous 4bp deletion in ARL6IP1 causing a frameshift in 1 consanguineous family with 2 siblings (both with age of onset at 14 months).

PMID: 31272422 - Wakil et al 2019 - report a consanguineous Saudi family with 2 siblings with a severe presentation of spastic paraplegia with many additional phenotypic components, which resulted in death of both affected siblings in early childhood. A homozygous nonsense variant ARL6IP1 (NM_015161.1: c.112C > T: p.Arg38*) was identified by homozygosity mapping and WES. The authors speculate that other variants may contribute to the severe clinical presentation in this family.

PMID: 30980493 - Chukhrova et al 2019 - report a consanguineous Russian family with 2 brothers with childhood onset spastic paraplegia. A homozygous variant c.[92T>C], p.[Leu31Pro] in ARL6IP1 was identified by WES. Sanger sequencing confirmed the variant was heterozygous in each parent.

PMID: 28471035 - Nizon et al 2018 - describe a patient with congenital insensitivity to pain, sensory neuropathy, acromutilation, and spastic paraplegia. Parents were second-cousins of Caucasian descent. A homozygous frameshift variant c.[577_580del], p.(Lys193Phefs*37) in ARL6IP1 was identified by WES (same variant as reported by Novarino). The unaffected mother and 1 sibling were heterozygous. Father's DNA was not available.

Created: 30 Jun 2021, 2:24 p.m. | Last Modified: 30 Jun 2021, 2:24 p.m.

Panel Version: 2.41

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 61, autosomal recessive, OMIM:615685

Publications

• 24482476
• 31272422
• 30980493
• 28471035

Green List (high evidence)

At least 4 families reported now.

Created: 16 Jun 2020, 10:54 a.m. | Last Modified: 16 Jun 2020, 10:54 a.m.

Panel Version: 2.12

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 61, autosomal recessive, MIM#615685

Publications

• 24482476
• 31272422
• 30980493
• 28471035

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

I don't know

Red gene with Green GLH rating, Gene discussed in view of discrepant rating(s) from GLH(s). Amber rating agreed at the GMS Neurology Specialist Test Group Webex on 17th May 2019.

Created: 21 May 2019, 4:50 p.m.

Green List (high evidence)

Appears to be childhood onset only. Two kindred reported but Novarino et al 2014 kindred with 4 affected individuals from 2 branches of family. No additional patients identified using Sheffield panel.

Created: 10 May 2019, 11:41 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
24482476; 28471035

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