Inheritance

Autosomal recessive

Prevalence

 <1 / 1 000 000

Source: ORPHA:557056

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - Definitive (AR), limited for (AD), 7/9/2021

Clinical Validity Scoring Notes and points

GLS was first reported in relation to autosomal recessive glutaminase deficiency in 2018 (Lynch DS, et al., 2018, PMID: 29468182). Glutaminase deficiency is characterized by refractory seizures, respiratory failure, brain abnormalities and death in the neonatal period, though milder cases with spastic ataxia-dysarthria have also been reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Five unique variants (nonsense, frameshift, and missense) have been reported as well as a 5’ UTR repeat expansion (normally occurring in 8 or 16 repeats) ranging from 680 to 1500 repeats. Variants in this gene have been reported in six probands in 3 publications (PMIDs: 29468182, 30575854, 30970188), and segregated with disease in at least 2 additional family member. Experimentally, this gene-disease relationship is supported by its role in the production of glutamate, the main excitatory neurotransmitter in the central nervous system, including the brain stem respiratory center (PMID: 12963351) and a mouse model with partial recapitulation of disease (PMID: 16641247). In summary GLS is definitively associated with autosomal recessive glutaminase deficiency.

Source: ClinGen

Clinical Validity Points Total

Source:

Clinical Validity Classification

Definitive

Source: ClinGen

Molecular Mechanism

Loss of function / decreased expression / methylation

Variant spectrum includes truncations, missense, triplet repeat expansions

Triplet repeat expansion of GCA in 5’UTR

• Normal: 5-26

• Pathogenic: ≥524

Cutoff:

Since there is such a large gap, suggest using a cutoff of ~40 (since this will reduce false positives for VA review, based on data in gnomAD). However Nirvana’s annotation sets normal range of 0-89. This cutoff is not really appropriate, as EH is not accurate when sizing alleles ~50 repeats and larger.

Sources: PMID: 30970188, 35913761

STR Review notes:

GeneReviews: Normal: 5-38, Full penetrance pathogenic 680-1500 https://www-ncbi-nlm-nih-gov.ezp-prod1.hul.harvard.edu/books/NBK535148/

• not sure where normal up to 38 came from

STRchive: "normal":"5-26", "pathogenic":"90 - 1500", "pathogenic_min":90.0, "pathogenic_max":1500.0

stripy - normal 5-26, ≥680

GnomAD - Normal ≤ 26, Pathogenic ≥ 680

van Kuilenburg 2019 PMID: 30970188

• Three probands with early onset motor delay, speech delay, ataxia. Elevation in plasma glutamine, normal plasma ammonia levels. Using ExpansionHunter, patient 1 was found to have an allele of more than 90 alleles (THIS IS WHERE THE CUTOFF OF 90 FOR EXPANDED ALLELES COMES FROM). Triplet repeat primed PCR performed on blood revealed that all three had expansions of the GCA repeat in the 5' UTR of GLS found in their blood samples (sized 680, 900, and 1500). Smaller repeats in fibroblasts consistent w/ somatic heterogeneity. To investigate normal repeat size 8295 genomes showed median size of 14 repeats.

Fazal 2023 PMID: 35913761

• Describes two families with Glutaminase deficiency. One with a complex structural change w/ a homozygous repeat expansion nested within a quadruplication event (family 1). Per fig 2E, the normal alleles are up to 29 repeats, and expanded alleles are as small as 524. Affected proband from family 2 cmp het frameshift and an expansion of ~1200 repeats

  • Normal repeats - 15, 29,

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Early childhood (2-4)

Source: STRchive (PMID: 30970188, 35913761)

Severity

Severe

Clinical Features

• Early onset gross and fine motor delay

• speech delay

• Ataxia (broad, ataxic gait)

• Normal brain MRI (or cerebellar atrophy at advanced stage)

• Progressive neuro deterioration

• tremor, dysarthria

• Optic atrophy, strabismus

• Epilepsy

• Metabolic testg: High plasma glutamine. Normal plasma ammonia, urinary organic acids and acylcarnities,

Sources: PMID: 30970188, 35913761

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 05.06.24https://broadinstitute.atlassian.net/browse/BCL-168