HK1 – Neurodevelopmental Disorder with Visual Defects and Brain Anomalies

Hexokinase 1 (HK1) has been implicated in a recently characterized neurodevelopmental disorder with visual defects and brain anomalies (Neurodevelopmental disorder with visual defects and brain anomalies). Clinical validity is supported by multiple unrelated de novo missense variants leading to a consistent phenotype of developmental delay, intellectual disability, visual impairment, elevated cerebrospinal fluid lactate, and basal ganglia MRI abnormalities.

Clinical Validity (Moderate)

Autosomal dominant inheritance is established by heterozygous de novo missense variants in HK1. To date, eleven unrelated probands (seven previously published (PMID:30778173); four in the current series (PMID:36639056)) present with a concordant neurodevelopmental and visual phenotype, without evidence of alternative genetic etiologies. Experimental data propose a gain-of-function mechanism through disruption of the regulatory glucose-6-phosphate binding site, supporting pathogenicity.

Genetic Evidence (Moderate)

Inheritance is autosomal dominant with exclusively de novo occurrence; no familial segregation beyond the proband (affected_relatives = 0). A total of eleven probands carry heterozygous missense variants clustering in the regulatory-terminal domain and α-helix of HK1. The variant spectrum to date comprises missense changes only, notably c.1981G>A (p.Asp661Asn) (PMID:36639056).

Functional Evidence (Limited)

Mechanistic studies suggest that these variants perturb glucose-6-phosphate binding, leading to a gain-of-function effect in neuronal tissue. No in vitro or in vivo functional assays specific to the neurodevelopmental phenotype have been reported, and direct demonstration of altered enzymatic or cellular activity in patient‐derived models remains outstanding.

Integration & Conclusion

The accumulation of de novo missense variants in HK1 with a consistent clinical presentation supports a moderate level of evidence for a gene–disease association. Additional functional studies and larger cohorts would strengthen the definitive classification. Key take-home: HK1 should be included in gene panels for unexplained neurodevelopmental disorders with visual impairment and brain anomalies.

References

• European journal of human genetics • 2019 • De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment. PMID:30778173
• European journal of medical genetics • 2023 • Expanding the neurodevelopmental phenotype associated with HK1 de novo heterozygous missense variants. PMID:36639056

Evidence Based Scoring (AI generated)