• Pan-Chung-Bellen syndrome

This report describes Pan-Chung-Bellen syndrome, a newly identified neurodevelopmental disorder in which de novo variants of the human gene FRYL have been implicated. Results to date are consistent with a dominant disorder with developmental and neurological symptoms due to haploinsufficiency. Little is known about the molecular function of FRYL or related genes. The orthologous gene in Drosophila is fry, for which multiple genetic reagents have been generated, including loss-of-function mutations, RNAi-targeting constructs, alleles caused by insertional mutagenesis, and overexpression constructs. Dmel/fry is also orthologous to the human gene FRY.

The human FRYL gene has not been introduced into flies; a human FRYL cDNA is not available primarily because the encoded protein is very large (3,013 amino acids).

In Drosophila, fry is predominantly expressed in neurons but not in glia in the fly central nervous system. Animals homozygous for severe loss-of-function mutations of fry die during embryonic or early larval stages. Dmel\fry knock-in alleles analogous to human FRYL disease-implicated missense variants have been created and characterized. See the 'Disease-Implicated Variants' table, below. Of four variants studied, one behaves as a severe loss-of-function variant and two behave as partial loss-of-function variants; one variant does not cause any observable defect in flies and may be reclassified as a variant of unknown significance.

[updated Mar. 2025 by FlyBase; FBrf0222196]