TY - JOUR
T1 - De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features
AU - Baylor College of Medicine Center for Precision Medicine Models
AU - Pan, Xueyang
AU - Tao, Alice M.
AU - Lu, Shenzhao
AU - Ma, Mengqi
AU - Hannan, Shabab B.
AU - Slaugh, Rachel
AU - Drewes Williams, Sarah
AU - O'Grady, Lauren
AU - Kanca, Oguz
AU - Person, Richard
AU - Carter, Melissa T.
AU - Platzer, Konrad
AU - Schnabel, Franziska
AU - Abou Jamra, Rami
AU - Roberts, Amy E.
AU - Newburger, Jane W.
AU - Revah-Politi, Anya
AU - Granadillo, Jorge L.
AU - Stegmann, Alexander P.A.
AU - Sinnema, Margje
AU - Accogli, Andrea
AU - Salpietro, Vincenzo
AU - Capra, Valeria
AU - Ghaloul-Gonzalez, Lina
AU - Brueckner, Martina
AU - Simon, Marleen E.H.
AU - Sweetser, David A.
AU - Glinton, Kevin E.
AU - Kirk, Susan E.
AU - Burrage, Lindsay C.
AU - Heaney, Jason D.
AU - Kim, Seon Young
AU - Lanza, Denise G.
AU - Liu, Zhandong
AU - Mao, Dongxue
AU - Milosavljevic, Aleksander
AU - Nagamani, Sandesh C.S.
AU - Posey, Jennifer E.
AU - Ramamurthy, Uma
AU - Ramanathan, Vivek
AU - Rogers, Jeffrey
AU - Rosenfeld, Jill A.
AU - Roth, Matthew
AU - Zahedi Darshoori, Ramin
AU - Wangler, Michael F.
AU - Yamamoto, Shinya
AU - Chung, Wendy K.
AU - Bellen, Hugo J.
N1 - Publisher Copyright:
© 2024 American Society of Human Genetics
PY - 2024/4/4
Y1 - 2024/4/4
N2 - 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.
AB - 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.
KW - Drosophila
KW - FRYL
KW - developmental delay
KW - furry
KW - intellectual disability
KW - rare disease
UR - http://www.scopus.com/inward/record.url?scp=85188995689&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2024.02.007
DO - 10.1016/j.ajhg.2024.02.007
M3 - Article
C2 - 38479391
AN - SCOPUS:85188995689
SN - 0002-9297
VL - 111
SP - 742
EP - 760
JO - American journal of human genetics
JF - American journal of human genetics
IS - 4
ER -