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Hum Mol Genet. 2018 Nov 26. doi: 10.1093/hmg/ddy406. [Epub ahead of print]

Biallelic variants in FBXL3 cause intellectual disability, delayed motor development and short stature.

Author information

1
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
2
Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan.
3
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
4
Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
5
Department of Medicine, KMU Institute of Medical Sciences, Kohat.
6
Radiology department, Lady reading Hospital, Peshawar.
7
Department of endocrinology diabetes and metabolism, University Hospital of Lausanne, Switzerland.
8
Department of Fundamental Oncology, Lausanne University, Ludwig Institute for Cancer Research, Route de la Corniche 9A, 1066 Epalinges, Switzerland.
9
Institut Jerome Lejeune, Paris, France.
10
Institute of Clinical Biochemistry, Faculty of Medicine, Catholic University IRCCS Policlinico Gemelli, Rome, Italy.
11
Center for the Study of Rare Hereditary Diseases, Niguarda Ca' Granda Metropolitan Hospital, Milan, Italy.
12
Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
13
iGE3 Institute of Genetics and Genomics of Geneva, Geneva, Switzerland.
14
Swiss Institute of Bioinformatics, Molecular Modeling Group, Batiment Genopode, Unil Sorge, Lausanne, Switzerland.

Abstract

FBXL3 (F-Box and Leucine Rich Repeat Protein 3) encodes a protein that contains an F-box and several tandem leucine-rich repeats (LRR) domains. FBXL3 is part of the SCF (Skp1-Cullin-F box protein) ubiquitin ligase complex that binds and leads to phosphorylation dependent degradation of the central clock protein cryptochromes (CRY1 and CRY2) by the proteasome and its absence causes circadian phenotypes in mice and behavioral problems. No FBXL3 related phenotypes have been described in humans. By a combination of exome sequencing and homozygosity mapping, we analyzed two consanguineous families with intellectual disability and identified homozygous LoF (loss-of-function) variants in FBXL3. In the first family, from Pakistan, an FBXL3 frameshift variant (NM_012158.2:c.885delT:p.(Leu295Phefs*25)) was the only segregating variant in five affected individuals in two family loops (LOD score: 3.12). In the second family, from Lebanon, we identified a nonsense variant (NM_012158.2:c.445C>T:p.(Arg149*). In a third patient from Italy, a likely deleterious non-synonymous variant (NM_012158.2:c.1072T>C:p.(Cys358Arg)) was identified in homozygosity. Protein 3D modeling predicted that the Cys358Arg change influences the binding with CRY2 by destabilizing the structure of the FBXL3, suggesting that this variant is also likely to be LoF. The eight affected individuals from the three families presented with a similar phenotype that included intellectual disability, developmental delay, short stature and mild facial dysmorphism, mainly large nose with a bulbous tip. The phenotypic similarity and the segregation analysis suggest that FBXL3 biallelic, loss-of-function variants link this gene with syndromic autosomal recessive developmental delay/intellectual disability.

PMID:
30481285
DOI:
10.1093/hmg/ddy406

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