Expanding the Allelic spectrum in ATP1A3-related disorders with 3 novel mutations and clinic features.

OBJECTIVES: To describe the complex phenotype of ATP1A3 and second to report new mutation of ATP1A3. METHODS: This is a retrospective chart review of 7 patients who was diagnosed with ATP1A3 mutation based on whole exome sequencing (WES) result and the following information were collected; age, age of onset, developmental ability, seizure type, family history, MRI, WES report. The data collection started a year ago January 2021 in King Faisal Specialist Hospital and Research Centre, Riyadh, KSA. This has been cleared for publication by the Office of Research Affairs, and the Publication Number is 2225429. RESULTS: Five females and 2 males had onset ages of 0-3 years (mean=18 months). All had some degree of intellectual dysfunction, 6 had seizures (85%), 4 had neurologic abnormalities, 1 had autistic features and one had mild dystonia. CONCLUSION: Our small-cohort observations confirm that ATP1A3 mutations express a wide range of phenotypes, usually including some degree of cognitive-behavioral dysfunction (100% of patients), seizures (85% of patients), and AHC (71% of patients). Moreover, they further expand the evolving allelic spectrum of these disorders by identifying 3 novel mutations.

SHQ1-associated neurodevelopmental disorder: Report of the first homozygous variant in unrelated patients and review of the literature.

Compound heterozygous mutations in SHQ1 have been associated with a rare and severe neurological disorder characterized by global developmental delay (GDD), cerebellar degeneration coupled with seizures, and early-onset dystonia. Currently, only five affected individuals have been documented in the literature. Here, we report three children from two unrelated families harboring a homozygous variant in the gene but with a milder phenotype than previously described. The patients had GDD and seizures. Magnetic resonance imaging analyses revealed diffuse white matter hypomyelination. Sanger sequencing confirmed the whole-exome sequencing results and revealed full segregation of the missense variant (SHQ1:c.833 T > C; p.I278T) in both families. We performed a comprehensive in silico analysis using different prediction classifiers and structural modeling of the variant. Our findings demonstrate that this novel homozygous variant in SHQ1 is likely to be pathogenic and leads to the clinical features observed in our patients.

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.