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BDV-syndrome: An emerging syndrome with profound obesity and neurodevelopmental delay resembling Prader-Willi syndrome
The Journal of Clinical Endocrinology & Metabolism ( IF 5.8 ) Pub Date : 2021-08-12 , DOI: 10.1210/clinem/dgab592
Elisabeth Bosch 1 , Moritz Hebebrand 1 , Bernt Popp 2 , Theresa Penger 3 , Bettina Behring 3 , Helen Cox 4 , Shelley Towner 5 , Cornelia Kraus 1 , William G Wilson 5 , Shagufta Khan 4 , Mandy Krumbiegel 1 , Arif B Ekici 1 , Steffen Uebe 1 , Regina Trollmann 3 , Joachim Woelfle 3 , André Reis 1 , Georgia Vasileiou 1
Affiliation  

Abstract
Context
CPE encodes carboxypeptidase E, an enzyme which converts proneuropeptides and propeptide hormones to bioactive forms. It is widely expressed in the endocrine and central nervous system. To date, four individuals from two families with core clinical features including morbid obesity, neurodevelopmental delay and hypogonadotropic hypogonadism, harbouring biallelic loss-of-function CPE variants, were reported.
Objective
We describe four affected individuals from three unrelated consanguineous families, two siblings of Syrian, one of Egyptian and one of Pakistani descent, all harbouring novel homozygous CPE loss-of-function variants.
Methods
After excluding Prader-Willi syndrome, exome sequencing was performed in both Syrian siblings. The variants identified in the other two individuals were reported as research variants in a large scale exome study and in ClinVar database. Computational modelling 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 two 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 indicated a recognisable clinical phenotype, which we termed Blakemore-Durmaz-Vasileiou (BDV) syndrome. Computational analysis indicated high conservation of CPE domains and intolerance to missense changes.
Conclusions
Biallelic truncating CPE variants are associated with BDV syndrome, a clinically recognisable monogenic recessive syndrome with childhood-onset obesity, neurodevelopmental delay, hypogonadotropic hypogonadism and hypothyroidism. BDV syndrome resembles Prader-Willi syndrome. Our findings suggested that missense variants may also be clinically relevant.


中文翻译:

BDV 综合征:一种具有严重肥胖和神经发育迟缓的新兴综合征,类似于 Prader-Willi 综合征

摘要
语境
CPE编码羧肽酶 E,这是一种将原神经肽和前肽激素转化为生物活性形式的酶。它在内分泌和中枢神经系统中广泛表达。迄今为止,报告了来自两个家族的四个人的核心临床特征,包括病态肥胖、神经发育迟缓和促性腺激素减退症,携带双等位基因功能丧失的CPE变异。
客观的
我们描述了来自三个不相关的近亲家庭的四个受影响的个体,两个叙利亚兄弟姐妹,一个埃及血统和一个巴基斯坦血统,都拥有新型纯合CPE功能丧失变体。
方法
排除 Prader-Willi 综合征后,对叙利亚兄弟姐妹进行了外显子组测序。在其他两个个体中发现的变异在大规模外显子组研究和 ClinVar 数据库中被报告为研究变异。所有可能的错义改变的计算建模允许评估CPE对错义变体的耐受性。
结果
所有受影响的个体都严重肥胖,伴有神经发育迟缓和其他内分泌异常。来自两个家族的三个个体共享相同的CPE纯合截断变异 c.361C>T, p.(Arg121*),而第四个携带 c.994del, p.(Ser333Alafs*22) 变异。将临床特征与先前描述的病例进行比较,并根据人类表型本体论进行标准化,表明存在可识别的临床表型,我们将其称为 Blakemore-Durmaz-Vasileiou (BDV) 综合征。计算分析表明 CPE 域的高度保守性和对错义变化的不容忍。
结论
双等位基因截断CPE变异与 BDV 综合征相关,这是一种临床上可识别的单基因隐性综合征,伴有儿童期肥胖、神经发育迟缓、促性腺激素减退症和甲状腺功能减退症。BDV 综合征类似于 Prader-Willi 综合征。我们的研究结果表明,错义变异也可能具有临床相关性。
更新日期:2021-08-12
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