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Homozygous deletion of MYADML2 in cranial asymmetry, reduced bone maturation, multiple dislocations, lumbar lordosis, and prominent clavicles

Journal of Human Genetics volume 66, pages 171–179 (2021)Cite this article

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Abstract

A null mutation in a patient can facilitate phenotype assignment and uncovers the function of that specific gene. We present five sibs of a consanguineous Pakistani family afflicted with a new syndrome with an unusual combination of skeletal anomalies including cranial asymmetry, fused sagittal sutures deviating from the medial axis, mandibular prognathia, maxillary hypoplasia, misaligned and crowded teeth, delayed bone age, multiple dislocations, hypoplastic and malpositioned patellae, humeral intracondylar fissures, scapular dyskinesis, long limbs, lumbar lordosis, protruding chest, prominent clavicles, short 5th digital rays, and ventral transverse digital creases plus features of cutis laxa. We mapped the disease gene locus to a 3.62-Mb region at 17q25.3 and identified a homozygous deletion of maximal 7.3 kb deduced to totally inactivate MYADML2 and downstream gene PYCR1, biallelic variants in which cause autosomal recessive cutis laxa (ARCL). All five affected sibs had the most common features of ARCL but not many of the less common ones. We attributed the anomalies not typical for ARCL to MYADML2 deficit, because no other genetic defect possibly a candidate to underlie the skeletal phenotype was found. MYADML2 is a gene of unknown function, has not been studied, and has not been associated with disease. Our findings present a possible phenotype for MYADML2 deficit that includes impaired bone patterning and maturation, definitely show that the gene is not essential for survival, and provide a start point for future studies on the function of MYADML2 protein. Detection of new patients is needed to confirm and delineate MYADML2-deficiency phenotype.

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Additional data that support the findings of this study are available from the corresponding authors upon request.

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Acknowledgements

We thank the family members for their cooperation. This study was supported by the Scientific and Technological Research Council of Turkey (114Z829 to AT) and URF-QAU Pakistan (QAU-URF-2017-18 to SM).

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Author notes

  1. These authors contributed equally: Esra Yıldız Bölükbaşı, Rana Muhammad Kamran Shabbir

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey

    Esra Yıldız Bölükbaşı

  2. Human Genetics Program, Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

    Rana Muhammad Kamran Shabbir & Sajid Malik

  3. Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul, Turkey

    Aslıhan Tolun

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  1. Esra Yıldız Bölükbaşı
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  2. Rana Muhammad Kamran Shabbir
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Contributions

Conception and design: AT and SM. Analysis and interpretation: EYB, SM, and AT. Clinical data collection: RMKS and SM. Obtained funding: AT and SM.

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Correspondence to Sajid Malik or Aslıhan Tolun.

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Yıldız Bölükbaşı, E., Shabbir, R.M.K., Malik, S. et al. Homozygous deletion of MYADML2 in cranial asymmetry, reduced bone maturation, multiple dislocations, lumbar lordosis, and prominent clavicles. J Hum Genet 66, 171–179 (2021). https://doi.org/10.1038/s10038-020-0817-8

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