BDV Syndrome: An Emerging Syndrome with Profound Obesity and Neurodevelopmental Delay Resembling Prader-Willi Syndrome

Bosch E, Hebebrand M, Popp B, Penger T, Behring B, Cox H, Towner S, Kraus C, Wilson WG, Khan S, Krumbiegel M, Ekici AB, Uebe S, Trollmann R, Wölfle J, Reis A, Vasileiou G (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Journal of Clinical Endocrinology and Metabolism Oxford University Press

Book Volume: 106

Pages Range: 3413-3427

Journal Issue: 12

DOI: 10.1210/clinem/dgab592

Abstract

Context: CPE encodes carboxypeptidase E, an enzyme that converts proneuropeptides and propeptide hormones to bioactive forms. It is widely expressed in the endocrine and central nervous system. To date, 4 individuals from 2 families with core clinical features including morbid obesity, neurodevelopmental delay, and hypogonadotropic hypogonadism, harboring biallelic loss-of-function (LoF) CPE variants, have been reported. Objective: We describe 4 affected individuals from 3 unrelated consanguineous families, 2 siblings of Syrian, 1 of Egyptian, and 1 of Pakistani descent, all harboring novel homozygous CPE LoF variants. Methods: After excluding Prader-Willi syndrome (PWS), exome sequencing was performed in both Syrian siblings. The variants identified in the other 2 individuals were reported as research variants in a large-scale exome study and in the ClinVar database. Computational modeling of all possible missense alterations allowed assessing CPE tolerance to missense variants. Results: All affected individuals were severely obese with neurodevelopmental delay and other endocrine anomalies. Three individuals from 2 families shared the same CPE homozygous truncating variant c.361C†>†T, p.(Arg121∗), while the fourth carried the c.994del, p.(Ser333Alafs∗22) variant. Comparison of clinical features with previously described cases and standardization according to the Human Phenotype Ontology terms indicated a recognizable clinical phenotype, which we termed Blakemore-Durmaz-Vasileiou (BDV) syndrome. Computational analysis indicated high conservation of CPE domains and intolerance to missense changes. Conclusion: Biallelic truncating CPE variants are associated with BDV syndrome, a clinically recognizable monogenic recessive syndrome with childhood-onset obesity, neurodevelopmental delay, hypogonadotropic hypogonadism, and hypothyroidism. BDV syndrome resembles PWS. Our findings suggest missense variants may also be clinically relevant.

Authors with CRIS profile

Elisabeth Bosch Professur für Humangenetik Moritz Hebebrand Lehrstuhl für Humangenetik Theresa Penger Professur für Kinderheilkunde mit dem Schwerpunkt Kinder-Endokrinologie und Diabetologie (Stiftungsprofessur) Bettina Behring Department of Paediatrics and Adolescent Medicine Mandy Krumbiegel Institute of Human Genetics Arif Bülent Ekici Lehrstuhl für Humangenetik Steffen Uebe Institute of Human Genetics Regina Trollmann Professur für Kinder- u. Jugendmedizin Schwerpunkt Neuropädiatrie Joachim Wölfle Lehrstuhl für Kinder- und Jugendmedizin André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Georgia Vasileiou Institute of Human Genetics

Involved external institutions

Universität Leipzig DE Germany (DE) Birmingham Women's and Children's NHS Foundation Trust GB United Kingdom (GB) University of Virginia (UVA) US United States (USA) (US)

How to cite

APA:

Bosch, E., Hebebrand, M., Popp, B., Penger, T., Behring, B., Cox, H.,... Vasileiou, G. (2021). BDV Syndrome: An Emerging Syndrome with Profound Obesity and Neurodevelopmental Delay Resembling Prader-Willi Syndrome. Journal of Clinical Endocrinology and Metabolism, 106(12), 3413-3427. https://doi.org/10.1210/clinem/dgab592

MLA:

Bosch, Elisabeth, et al. "BDV Syndrome: An Emerging Syndrome with Profound Obesity and Neurodevelopmental Delay Resembling Prader-Willi Syndrome." Journal of Clinical Endocrinology and Metabolism 106.12 (2021): 3413-3427.

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