PUBLICATION

Alu-Alu mediated intragenic duplications in IFT81 and MATN3 are associated with skeletal dysplasias

Authors
Pettersson, M., Vaz, R., Hammarsjö, A., Eisfeldt, J., Carvalho, C.M.B., Hofmeister, W., Tham, E., Horemuzova, E., Voss, U., Nishimura, G., Klintberg, B., Nordgren, A., Nilsson, D., Grigelioniene, G., Lindstrand, A.
ID
ZDB-PUB-180807-9
Date
2018
Source
Human Mutation   39(10): 1456-1467 (Journal)
Registered Authors
Vaz, Raquel
Keywords
IFT81, Jeune syndrome, MATN3, intragenic duplication, multiple epiphyseal dysplasia, whole genome sequencing, zebrafish
MeSH Terms
  • Muscle Proteins/genetics*
  • Gene Duplication*
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations
  • Zebrafish
  • Ellis-Van Creveld Syndrome/diagnosis
  • Ellis-Van Creveld Syndrome/genetics
  • Male
  • Animals
  • Radiography
  • Osteochondrodysplasias/diagnosis*
  • Osteochondrodysplasias/genetics*
  • Whole Genome Sequencing
  • Phenotype
  • Child
  • Female
  • Alu Elements*
  • Genetic Association Studies*
  • Humans
  • Adolescent
  • Matrilin Proteins/genetics
  • Pedigree
  • Homozygote
(all 23)
PubMed
30080953 Full text @ Hum. Mutat.
Abstract
Skeletal dysplasias are a diverse group of rare mendelian disorders with clinical and genetic heterogeneity. Here, we used targeted copy number variant (CNV) screening and identified intragenic exonic duplications, formed through Alu-Alu fusion events, in two individuals with skeletal dysplasia and negative exome sequencing results. First, we detected a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD) (MIM# 208500). Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Complementary zebrafish studies suggested that loss of full-length IFT81 protein but expression of a shorter form of IFT81 protein affects the phenotype while being compatible with life. Second, a de novo tandem duplication of exons 2 to 5 in MATN3 was identified in a girl with multiple epiphyseal dysplasia (MED) type 5 (MIM# 607078). Our data highlights the importance of detection and careful characterization of intragenic duplication CNVs, presenting them as a novel and very rare genetic mechanism in IFT81-related Jeune syndrome and MATN3-related MED. This article is protected by copyright. All rights reserved.
Genes / Markers
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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Citation
Pettersson, M., Vaz, R., Hammarsjö, A., Eisfeldt, J., Carvalho, C.M.B., Hofmeister, W., Tham, E., Horemuzova, E., Voss, U., Nishimura, G., Klintberg, B., Nordgren, A., Nilsson, D., Grigelioniene, G., Lindstrand, A. (2018) Alu-Alu mediated intragenic duplications in IFT81 and MATN3 are associated with skeletal dysplasias. Human Mutation. 39(10):1456-1467.