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Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes
  1. Beyhan Tuysuz1,
  2. Dilek Uludag Alkaya1,
  3. Filiz Geyik1,2,
  4. Merve Alaylıoğlu3,
  5. Busra Kasap1,2,
  6. Sebuh Kurugoğlu4,
  7. Yunus Emre Akman5,
  8. Mehmet Vural6,
  9. Kaya Bilguvar7
  1. 1 Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey
  2. 2 Department of Genetics, Aziz Sancar Experimental Medicine Research Institute, Istanbul University, Istanbul, Turkey
  3. 3 Institute of Neurological Sciences, Brain and Neurodegenerative Disorders Research Laboratory, Istanbul University-Cerrahpasa, Istanbul, Turkey
  4. 4 Department of Pediatric Radiology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey
  5. 5 Department of Orthopedics and Traumatology, University of Health Sciences Turkey, Baltalimani Bone Diseases Training and Research Center, Istanbul, Turkey
  6. 6 Department of Neonatology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey
  7. 7 Departments of Neurosurgery and Genetics, Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut, USA
  1. Correspondence to Dr Beyhan Tuysuz, Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey; beyhan{at}


Background Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders characterised by susceptibility to fractures, primarily due to defects in type 1 collagen. The aim of this study is to present a novel OI phenotype and its causative candidate gene.

Methods Whole-exome sequencing and clinical evaluation were performed in five patients from two unrelated families. PHLDB1 mRNA expression in blood and fibroblasts was investigated by real-time PCR, and western blot analysis was further performed on skin fibroblasts.

Results The common findings among the five affected children were recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment. We identified biallelic NM_001144758.3:c.2392dup and NM_001144758.3:c.2690_2693del pathogenic variants in PHLDB1 in the affected patients, respectively, in the families; parents were heterozygous for these variants. PHLDB1 encodes pleckstrin homology-like domain family B member-1 (PHLDB1) protein, which has a role in insulin-dependent Akt phosphorylation. Compared with controls, a decrease in the expression levels of PHLDB1 in the blood and skin fibroblast samples was detected. Western blot analysis of cultured fibroblasts further confirmed the loss of PHLDB1.

Conclusion Two biallelic frameshift variants in the candidate gene PHLDB1 were identified in independent families with a novel, mild-type, autosomal recessive OI. The demonstration of decreased PHLDB1 mRNA expression levels in blood and fibroblast samples supports the hypothesis that PHLDB1 pathogenic variants are causative for the observed phenotype.

  • osteopathic medicine
  • heredity
  • molecular diagnostic techniques
  • mutation
  • radiology

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • Contributors Planning and conduct: BT, KB. Conception and design of the study: BT, DUA, KB. Acquisition of data or analysis and interpretation of data: BT, DUA, FG, MA, BK, SK, YEA. Drafting the manuscript and writing: DUA, MV, BT. Guarantor: BT.

  • Funding This work was supported by the Turkish Pediatric Association (grant number 04/14.2.2019) and the Scientific and Technological Research Council of Turkey (TUBITAK) (grant number 217S378 to BT).

  • 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.