Genetics of GH Deficiency: Insights From a Cohort of 203 Patients.
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Ribeiro Ana Cláudia, Coutinho Eduarda, Syed Najeeb, Bastos Margarida, Bacelar Conceição, Costa Carla, Freitas Paula, Gomes Leonor, Agapito Ana, Fonseca Fernando, Amaral Daniela, Carvalho Davide, Sampaio Maria Lurdes, Pereira Bernardo Dias, Antunes Ana Maria, Leite Valeriano, Castro João Jácome, Barros Luísa, Pina Rosa, Martins Sofia Almeida, Martinho Mariana, Martins Diana, Luiz Henrique Vara, Mirante Alice, Lopes Lurdes, Limbert Catarina, Pereira Carla, Gomes Maria Miguel, Cardoso Helena, Dinis Isabel, Paiva Sandra, Gonçalves Catarina Inês, Saraiva Luís R, Lemos Manuel Carlos
Аннотация
OBJECTIVE: To determine the genetic basis of GH deficiency in a Portuguese cohort.
DESIGN, SETTING, PATIENTS: Multicenter cohort of 203 GH-deficient patients (78 with isolated GH deficiency and 125 with combined pituitary hormone deficiency) were analyzed.
INTERVENTION: Screening of a panel of 184 GH deficiency-related genes using Sanger sequencing and whole exome sequencing.
MAIN OUTCOME MEASURE: Rare sequence variants (population maximum allele frequency <0.01).
RESULTS: A genetic cause was identified in 23.2% of patients (9.0% in isolated GH deficiency and 32.0% in combined pituitary hormone deficiency). Mutations were found in the PROP1 (14.8% of patients), GLI2 (2.0%), KMT2D (1.0%), PROK2 (1.0%), PROKR2 (1.0%), CDON (0.5%), COL1A2 (0.5%), COL2A1 (0.5%), GHRHR (0.5%), PTPN11 (0.5%), and SOX3 (0.5%) genes. One patient (0.5%) had a digenic mutation in the BMP4 and NF1 genes. Variants of uncertain significance were identified in 87.8% of patients.
CONCLUSION: This study revealed several novel and recurrent mutations that expand the genetic spectrum of GH deficiency and underscore the genetic heterogeneity of this disorder. A significant proportion of patients remained genetically undiagnosed, suggesting the involvement of additional unknown genetic, epigenetic, or environmental factors. These findings contribute to the understanding of the genetic architecture of GH deficiency and highlight the need for further investigations to elucidate underlying mechanisms and identify additional causative factors.