Abstract only
The Cobalamin activation disorders (CblA‐CblG) are deleterious inborn errors of Vitamin B
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activation, resulting in severe intellectual disability, vision impairment, and seizures. ...Although cobalamin activation disorders are exceedingly rare, typically occurring 1 in every 200,000 births, Phoenix Children's Hospital has an unusually high number of patients (n=21). We conducted a retrospective, exploratory examination of medical records to identify symptom trends in individuals clinically diagnosed with CblC (n=16) in relation to race, ethnicity, and tribal affiliation. This study is unique due to our direct access to a large population of children with this condition, the majority of whom are Native American (n=6) or Hispanic (n=8), while the remaining 2 are of Caucasian descent. We also examined the symptoms of two Native American children believed to have a novel mutation related to cobalamin metabolism. Of the 16 individuals clinically diagnosed with CblC, those with the most severe eye abnormalities tended to be of Athabascan descent. In addition, growth delays were present in 5 children, with no apparent connection to race or ethnicity. Finally, two children believed to exhibit a novel mutation related to cobalamin activation, who are both of the same Native American tribal (non‐Athabascan) descent, display no ophthalmological symptoms. Findings from this study will expand the clinical understanding of this disease and will shed light on the impact of these conditions in minority populations. In addition, these results lay the foundation for future research examining associations between symptoms, symptom severity, and genetic analysis data. The ultimate goal of this research is to contribute to the Cobalamin activation section of a gene chip that addresses genetic disorders in Native Americans.
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Phoenix Children's Hospital
The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation ...of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO.
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