Lipodystrophy - childhood onset

Gene: PIK3R1

Green List (high evidence)

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

Created: 31 Dec 2025, 7:17 p.m. | Last Modified: 31 Dec 2025, 7:17 p.m.

Panel Version: 4.66

This gene is approved to upgrade to Green when TD eligibility and Clinical Indication name is expanded to Severe insulin resistance and lipodystrophy syndromes.

Created: 17 Jun 2024, 8:59 a.m. | Last Modified: 17 Jun 2024, 8:59 a.m.

Panel Version: 4.54

Comment on list classification: There is sufficient evidence available for the association of this gene with lipodystrophy and insulin resistance and hence this gene can be promoted to green rating at the next GMS review.

Created: 2 Aug 2023, 1:49 p.m. | Last Modified: 2 Aug 2023, 1:49 p.m.

Panel Version: 4.6

PMID:23810378 - Nine affected individuals from eight different families were identified with de novo or inherited PIK3R1 variants, including a mutational hotspot (c.1945C>T/ p.Arg649Trp) present in four families. Insulin resistance was present in seven individuals and lipoatrophy was present in 3 individuals.

PMID:26497935 - Clinical reappraisal of detailed phenotypes of 32 individuals with PIK3R1-associated SHORT syndrome showed that IUGR <= 3rd percentile (19/25), postnatal growth retardation (height < -2SD, 25/31), lipoatrophy (26/29), factual dysmorphism (all 32 cases) and insulin resistance (13/17) are the main features of this disease.

PMID:27766312 - Five patients were reported with SHORT syndrome and C-terminal variants in PIK3R1, of which four had extreme insulin resistance without dyslipidemia or hepatic steatosis.

This gene has been associated with relevant phenotypes in both OMIM (MIM #269880) and Gene2Phenotype ('definitive' rating in the DD panel). Both lipoatrophy (lower face, upper limb, buttock) and insulin resistance diabetes has been associated as clinical manifestations of this OMIM phenotype for SHORT syndrome.

Created: 2 Aug 2023, 1:47 p.m. | Last Modified: 2 Aug 2023, 1:47 p.m.

Panel Version: 4.3

This gene was added on recommendation of NHSE Genomic Medicine Service. Below are the comments from NHS:

PanelApp expert review green (https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!) Co-segregates with disease in multiple independent pedigrees (PMID: 27766312, 23810378, 26497935), its gene product is a member of the canonical insulin signalling cascade and has been endorsed as a cause of lipodystrophy by an international multi-society practice guideline (PMID: 27710244).

SHORT syndrome appears to be caused by C-Terminal mutations affecting the SH2 domain, suggesting a mechanism other than simple loss of function (see Prof Rob Semple's review in Panel app @ https://panelapp.genomicsengland.co.uk/panels/174/gene/PIK3R1/#!)

Created: 2 Aug 2023, 11:35 a.m. | Last Modified: 2 Aug 2023, 11:51 a.m.

Panel Version: 4.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
SHORT syndrome, partial lipodystrophy, severe insulin resistance

Publications

• 23810378
• 26497935
• 27710244
• 27766312

Mode of pathogenicity
Other