De Novo Variants in FRMD5 Are Associated With Developmental Delay, Intellectual Disability, Ataxia, and Abnormalities of Eye Movement

Authors

Shenzhao Lu
Mengqi Ma
Xiao Mao
Carlos A Bacino
Joseph Jankovic
V Reid Sutton
James A Bartley
Xueying Wang
Jill A Rosenfeld
Ana Beleza-Meireles
Jaynee Chauhan
Xueyang Pan
Megan Li
Pengfei Liu
Katrina Prescott
Sam Amin
George Davies
Michael F Wangler
Yuwei Dai
Hugo J Bellen

Publication Date

10-6-2022

Journal

The American Journal of Human Genetics

DOI

10.1016/j.ajhg.2022.09.005

PMID

36206744

PMCID

PMC9606480

PubMedCentral® Posted Date

10-6-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Ataxia, DNA, Complementary, Developmental Disabilities, Eye Movements, Humans, Intellectual Disability, Membrane Proteins, Phosphatidylinositols, Seizures, Tumor Suppressor Proteins, FRMD5, Drosophila, CG5022, dFrmd, developmental delay, intellectual disability, ataxia, seizures, nystagmus, opsoclonus

Abstract

Proteins containing the FERM (four-point-one, ezrin, radixin, and moesin) domain link the plasma membrane with cytoskeletal structures at specific cellular locations and have been implicated in the localization of cell-membrane-associated proteins and/or phosphoinositides. FERM domain-containing protein 5 (FRMD5) localizes at cell adherens junctions and stabilizes cell-cell contacts. To date, variants in FRMD5 have not been associated with a Mendelian disease in OMIM. Here, we describe eight probands with rare heterozygous missense variants in FRMD5 who present with developmental delay, intellectual disability, ataxia, seizures, and abnormalities of eye movement. The variants are de novo in all for whom parental testing was available (six out of eight probands), and human genetic datasets suggest that FRMD5 is intolerant to loss of function (LoF). We found that the fly ortholog of FRMD5, CG5022 (dFrmd), is expressed in the larval and adult central nervous systems where it is present in neurons but not in glia. dFrmd LoF mutant flies are viable but are extremely sensitive to heat shock, which induces severe seizures. The mutants also exhibit defective responses to light. The human FRMD5 reference (Ref) cDNA rescues the fly dFrmd LoF phenotypes. In contrast, all the FRMD5 variants tested in this study (c.340T>C, c.1051A>G, c.1053C>G, c.1054T>C, c.1045A>C, and c.1637A>G) behave as partial LoF variants. In addition, our results indicate that two variants that were tested have dominant-negative effects. In summary, the evidence supports that the observed variants in FRMD5 cause neurological symptoms in humans.