Optic neuropathy

Gene: HK1

Comment on list classification: This gene should be promoted to Green at the next GMS panel update. Optic atrophy identified in 5/7 patients reported to date with HK1-related neurodevelopmental disorder (AD inheritance).

Created: 3 Nov 2022, noon | Last Modified: 3 Nov 2022, noon

Panel Version: 2.78

Comment on mode of inheritance: Setting to 'monoallelic' as this is the appropriate MOI for this panel (MIM# 618547). Incorrect biallelic MOI was copied from ID panel which will be rectified following GMS approval (Q3_22).

Created: 3 Nov 2022, 11:59 a.m. | Last Modified: 3 Nov 2022, 11:59 a.m.

Panel Version: 2.77

Green List (high evidence)

Based on the review by K Varvagiannis I think this gene should have monoallelic inheritance in regard to ID/DD, rather than biallelic. Biallelic variants are associated with haemolytic anaemia or neuropathy as the primary features - covered by other panels. Het de novo missense in the N-terminal half of the gene are reported in a neurodevelopmental disorder associated with developmental delay, intellectual disability, structural brain abnormality, and visual impairments.

Created: 21 Sep 2022, 9:59 a.m. | Last Modified: 21 Sep 2022, 9:59 a.m.

Panel Version: 3.1720

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual disability; developmental delay, delayed speech and language, learning disability

Publications

• 30778173

Comment on list classification: Promoted from red to green. This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There are sufficient cases for this gene to be promote to green status. Variants on the 5' end of the gene have been associated with neuropathy, hereditary motor and sensory, Russe type.

Created: 9 Jul 2019, 4:13 p.m. | Last Modified: 9 Jul 2019, 4:13 p.m.

Panel Version: 2.949

Comment on mode of pathogenicity: A gain of function effect is presumed to cause disease.

Created: 9 Jul 2019, 4:08 p.m. | Last Modified: 9 Jul 2019, 4:08 p.m.

Panel Version: 2.948

Green List (high evidence)

Okur et al. (2019 - PMID: 30778173) report on 7 individuals from 6 unrelated families, all harboring de novo HK1 variants. The common phenotype consisted among others of DD (7/7), ID (5/5 - the other 2 individuals were too young to evaluate), visual impairment (7/7 - optic atrophy and/or retinitis pigmentosa) and brain MRI abnormalities (6/7). Other features included tone abnormalities, delayed/impaired speech, ataxia, feeding problems, etc.

All variants were missense and occurred as de novo events. The following 4 variants were reported (using NM_000188.2 as reference):
- c.1241G>A p.(Gly414Glu)
- c.1252A>G p.(Lys418Glu)
- c.1334C>T p.(Ser445Leu) [observed in 2 unrelated individuals]
- c.1370C>T p.(Thr457Met) [observed in 2 sibs as well as well as a 3rd affected unrelated subject, the parents of the sibs and a further unaffected child from the same family were not found to harbor the variant]

As commented on, NM_000188.2:c.1334C>T p.(Ser445Leu) [or NM_033497.2:c.1346C>T (p.Ser449Leu)] and NM_000188.2:c.1370C>T p.(Thr457Met) [or NM_033497.2:c.1382C>T (p.Thr461Met)] were recurrent variants in this study and previously reported in 2 additional subjects from the DDD study (where 4 de novo variants were observed in total - PMID: 28135719). [All relevant DDD subjects are summarized in the denovo-db : http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=HK1]HK1].

HK1 encodes hexokinase 1. Hexokinases catalyze the first step in glucose metabolism (glycolytic pathway), using ATP as phosphate donor for the phosphorylation of glucose to glucose-6-phosphate (G6P). The 4 hexokinases (the 3 other - HK2, HK3 and HK4 - being encoded by other genes) vary in tissue distribution and other properties. HK1 has the predominant glucose phosphorylating activity in tissues with strict dependence on glucose utilization for their physiologic functions, such as brain, erythrocytes, etc (better summarized by Bianchi et al. - PMID: 9197463). Different HK1 isoforms exist, with the canonical one expressed ubiquitously and known as "brain-type hexokinase" due to its abundance in brain (summarized by Okur et al).

All aforementioned variants affect all HK1 isoforms. In silico predictions were (mostly) suggestive of pathogenicity. The variants were absent from ExAC/gnomAD databases (where HK1 has a pLI of 0.91 and Z-score of 3.34).

Hexokinase activity in RBCs from 2 affected subjects was found to be normal (as has also been the case for HK1-related phenotypes other than non-spherocytic anemia - details below). A gain-of-function effect is presumed. No additional studies have been carried out.

Based on this study and OMIM, previously reported HK1-related phenotypes include:
- Bi-allelic HK1 variants affecting hexokinase activity cause Hemolytic anemia (HA) due to hexokinase deficiency (MIM 235700). On 5 occasions neurodevelopmental phenotypes have been reported in individuals with this diagnosis although - as suggested - not all cases were molecularly confirmed and/or these findings might have been secondary to intrauterine consequences of HA or coincidental (PMIDs cited by Okur et al - table 3 : 5076409, 655151, 4052330, 12211198, 27282571).
- Homozygous 5' UTR variants have been associated with Neuropathy, hereditary motor and sensory, Russe type (MIM 605285).
- A missense variant (c.2539G>A or p.Glu847Lys) close to the C-terminal end has been reported in several occurences of (AD) retinitis pigmentosa 79 (MIM 617460) segregating with the disorder. Asymptomatic heterozygous carriers have also been reported. One patient homozygous for this variant presented with early-onset visual impairment but without hemolytic anemia or developmental anomalies.
---------
HK1 is not associated with any phenotype in G2P.
The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx - among the authors of the study).
---------
As a result this gene can be considered for upgrade to green (DD/ID in 7 individuals or possibly more when considering the DDD study participants) or amber (no functional evidence).

Created: 24 Feb 2019, 9:46 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Abnormal muscle tone, Global developmental delay, Intellectual disability, Visual impairment, Neurological speech impairment, Ataxia

Publications

• 30778173
• 28135719

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

Comment on mode of inheritance: Leaving the MOI as biallelic for now but with the recommendation of changing to monallelic following GMS review.

Created: 28 Sep 2022, 5:25 p.m. | Last Modified: 28 Sep 2022, 5:25 p.m.

Panel Version: 3.1729

As noted by Tracy Lester, the cases reported by Okur et al. 2019 - PMID: 30778173 are have heterozygous de novo variants in HK1 and a phenotype of developmental delay, intellectual disability, structural brain abnormality, and visual impairments, therefore the mode of inheritance should be changed from biallelic to monoallelic.

Created: 28 Sep 2022, 5:23 p.m. | Last Modified: 28 Sep 2022, 5:23 p.m.

Panel Version: 3.1727

Comment on list classification: Associated with Hemolytic anemia due to hexokinase deficiency (MIM:235700), Neuropathy, hereditary motor and sensory, Russe type (MIM:605285) and Retinitis pigmentosa 79 (MIM:617460) in OMIM. No evidence found of association with Intellectual Disability in OMIM, Gene2Phenotype or PubMed searches.

Created: 21 Feb 2018, 10:59 a.m.

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_movement_disorder_list . Main mutation mechanism : NA

Created: 27 Jul 2017, 6:34 p.m.

Evidences key, gene present in following gene lists and main mutation mechanism : manju_list; neuro_20160418_strict; NA. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust

Created: 19 Jul 2017, 12:37 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• Personal communication with NIHRBRRD BRIDGE SPEED

Comment on list classification: This gene is from an expert list and needs further assessment by the Genomics England curation team to assess inclusion and pertinence to this panel.

Created: 20 Jul 2017, 11:59 a.m.