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Novel disease loci
Original research
Developmental dysplasia of the hip caused by homozygous TRIM33 pathogenic variant affecting downstream BMP pathway
  1. Maya Gombosh1,
  2. Regina Proskorovski-Ohayon1,
  3. Yuval Yogev1,
  4. Marina Eskin-Schwartz1,2,
  5. Noam Hadar1,
  6. Sarit Aharoni1,
  7. Vadim Dolgin1,
  8. Eugen Cohen3,
  9. Ohad S Birk1,2
  1. 1 Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
  2. 2 Institute for Human Genetics, Soroka Medical Center, Beer Sheva, Israel
  3. 3 Department of Orthopedics, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
  1. Correspondence to Dr Ohad S Birk; obirk{at}bgu.ac.il

Abstract

Background Developmental dysplasia of the hip (DDH), formerly termed congenital dislocation of the hip, is the most common congenital disease of the musculoskeletal system in newborns. While familial predilection to DDH has been well documented, the molecular genetics/pathways of this common disorder are poorly understood.

Methods Linkage analysis and whole exome sequencing; real-time PCR studies of skin fibroblasts.

Results Consanguineous Bedouin kindred presented with DDH with apparent autosomal recessive heredity. Linkage analysis and whole exome sequencing delineated a single 3.2 Mbp disease-associated chromosome 1 locus (maximal multipoint Logarithm of the Odds score 2.3), containing a single homozygous variant with a relevant expression pattern: addition of threonine in TRIM33 (NM_015906.4); c.1648_1650dup. TRIM33 encodes a protein that acts both in the TGF-β and the BMP pathways; however, it has been mostly studied regarding its function in the TGF-β pathway. Since BMPs are known to act in bone formation, we focused on the BMP pathway, in which TRIM33 functions as a transcription factor, both an activator and repressor. Skin fibroblasts of two affected girls and a heterozygous TRIM33 variant carrier were assayed through reverse-transcription PCR for expression of genes known to be downstream of TRIM33 in the BMP pathway: fibroblasts of affected individuals showed significantly reduced expression of DLX5, significantly increased expression of BGLAP, increased expression of ALPL and no change in expression of RUNX2 or of TRIM33 itself.

Conclusions DDH can be caused by a biallelic variant in TRIM33, affecting the BMP pathway.

  • Mutation
  • Exome Sequencing

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/jmg-2024-109928

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • X @yogevyu, @OhadBirk

    • Contributors Study conception, planning, design, conduct, writing the manuscript: MG, EC, OSB. Data interpretation: MG, EC, OSB, ME-S, YY, NH. Data acquisition: MG, RP-O, SA, EC, VD, ME-S. Author acting as guarantor: OSB.

    • Funding The study was funded by the Morris Kahn Family Foundation, The Israel Science Foundation grant 2463/23, and the Israeli Ministry of Science and Technology National Center for Rare Diseases.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.