De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features.

FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are confirmed de novo in all individuals except one. Human genetic data suggest that FRYL is intolerant to loss of function (LoF). We find that the fly FRYL ortholog, furry (fry), is expressed in multiple tissues, including the central nervous system where it is present in neurons but not in glia. Homozygous fry LoF mutation is lethal at various developmental stages, and loss of fry in mutant clones causes defects in wings and compound eyes. We next modeled four out of the five missense variants found in affected individuals using fry knockin alleles. One variant behaves as a severe LoF variant, whereas two others behave as partial LoF variants. One variant does not cause any observable defect in flies, and the corresponding human variant is not confirmed to be de novo, suggesting that this is a variant of uncertain significance. In summary, our findings support that fry is required for proper development in flies and that the LoF variants in FRYL cause a dominant disorder with developmental and neurological symptoms due to haploinsufficiency.

Clinical case report of intractable paroxysmal sympathetic hyperactivity in TANGO2 deficiency disorder.

TANGO2 deficiency disorder (TDD) is a neurodegenerative disease characterized by a broad and variable spectrum of clinical manifestations, even among individuals sharing the same pathogenic variants. Here, we report a severely affected individual with TDD presenting with intractable paroxysmal sympathetic hyperactivity (PSH). While progressive brain atrophy has been observed in TDD, PSH has not been reported. Despite comprehensive workup for an acute trigger, no definite cause was identified, and pharmacological interventions were ineffective to treat PSH. Ultimately care was redirected to comfort measures. This article expands the clinical phenotype of patients with TDD, highlights the possibility of PSH in these patients, and the need for continued research for better treatments of TDD.