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.

The phenotypic and genotypic spectrum of individuals with mono- or biallelic ANK3 variants.

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms.

Rare Coronary Artery Variants are Associated with Increased Mortality and Reinterventions Following the Arterial Switch Operation.

OBJECTIVE: To determine the influence of coronary anatomy on long-term outcomes of the arterial switch operation (ASO). METHODS: We retrospectively reviewed patients with transposition of the great arteries or Taussig-Bing anomaly who underwent ASO at our institution between 1992 and 2022. The primary endpoint was freedom from a composite of death, transplant, or coronary reintervention. RESULTS: A total of 632 patients (median age: 5.0 days [IQR, 4.0-7.0]) underwent ASO. Coronary anatomy included: usual (n=411, 65%), circumflex from sinus 2 (n=89, 14%), inverted (n=55, 9%), single sinus (n=46, 7%), and intramural (n=31, 5%). Overall operative mortality was 3% (n=16) and highest among intramurals (n=3, 10%), though dropped to 0% in this group in the most recent decade. Median follow-up was 14.5 years [IQR, 6.0-20.3]. Twenty-year freedom from the primary endpoint was 95%±1% for usual anatomy, 99%±1% for circumflex from sinus 2, 90%±4% for inverted, 91%±4% for single sinus, and 80%±9% for intramural (P<0.001). Intramurals had the highest 20-year incidence of coronary reintervention (11%±8%). Cox modeling identified intraoperative coronary revision (HR 20.1, 95% CI:[9.4-53.9], P<0.001), Taussig-Bing anomaly (HR 4.9, 95% CI:[2.2-10.9], P<0.001), and an intramural coronary artery (HR 2.9, 95% CI: [1.0-8.2], P=0.04) to be risk factors for the composite endpoint. CONCLUSIONS: Rare coronary artery variants-particularly intramural-are associated with increased mortality and coronary reinterventions after ASO. A low threshold for unroofing intramurals is likely associated with declining mortality and improved outcomes. Additional investigations are required to determine the long-term fate of the coronary arteries after ASO.