ITPA was first reported in relation to autosomal recessive developmental and epileptic encephalopathy in 2015 (Kevelam et al., PMID: 26224535). Developmental and epileptic encephalopathy (DEE) is a neurodevelopmental disorder characterized by onset of seizures early in life along with delays in development. Other individuals with monoallelic or biallelic variants in ITPA may present with inosine triphosphate pyrophosphohydrolase (ITPase) deficiency, which is a common condition characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes (PMIDs: 12436200, 12384777). These patients are otherwise asymptomatic and do not present with any developmental delays nor with epilepsy. When evaluating these conditions, we found differences in inheritance pattern between individuals with DEE and individuals with isolated ITPase deficiency; individuals with ITPase deficiency may have monoallelic or biallelic variants, whereas individuals with DEE presented solely with biallelic ITPA variants. Additionally, we found a strong difference in phenotypic variability between these patients. Individuals reported with isolated ITPase deficiency were asymptomatic, whereas DEE is an often severe neurodevelopmental disorder with childhood onset. Currently, the molecular mechanism underlying these different phenotypic presentations is not well understood. However, the current hypothesis is that DEE is the result of putative loss of function or destruction of crucial binding sites (PMID: 34989426). Therefore, per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have decided to split these disease assertions and will not be including individuals with isolated ITPase deficiency in this curation for DEE.
Six variants (nonsense, frameshift, splice site, missense, single exon deletion) that have been reported in seven probands in three publications are included in this curation (PMIDs: 26224535, 34989426, 33593863). In addition to epilepsy and developmental delays, patients commonly present with microcephaly and hypotonia. Patients may also exhibit delayed myelination and mild to moderate cerebral atrophy on brain MRIs. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, there is definitive evidence supporting the relationship between ITPA and autosomal recessive developmental and epileptic encephalopathy (MONDO:0100062). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on the meeting date February 6, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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