PRECISION DIAGNOSIS OF GROWTH-RELATED MENDELIAN DISORDERS

Abstract

Growth disorders are conditions that restrict the child’s ability to grow normally, resulting in impaired linear growth, inadequate weight gain, delayed skeletal maturation, and other characteristics of varying degrees. These can be due to genetic factors, hormonal disorders, chronic diseases, malnutrition or endocrine diseases. Most of the affected patients have a height below -2 standard deviation (SD) (short stature) or -3SD (extreme short stature) and weight below -2SD (underweight) according to their age, gender and ethnicity. There are more than 1,330 Mendelian disorders in which growth issues are the main clinical phenotype. The aim of this research project is to investigate the clinical and genetic features of individuals with growth-related disorders in Qatar through whole genome sequencing and bioinformatics analysis. Variant filtration was applied based on family pedigree, Mendelian inheritance pattern, allele frequencies, etc. to identify variants from a manually curated list of over 900 genes known to be associated with growth-related disorders. Molecular docking using HADDOCK and simulation was additionally used to explore the functional impact of the variants. We identified causative variants for 13 patients (86%) with growth-related Mendelian disorders due to impaired linear growth and inadequate weight gain. Particularly, variants associated with SHOX-related short stature in 30% of the cases, variants in the GH/IGF-1 axis in 23% of the cases, and in 46% of the patients, genetic variants associated with rare growth-related Mendelian disorders were identified. A precise diagnosis will facilitate the determination of the appropriate treatment, reduce side effects, and monitor complications. Moreover, it will enable the accurate estimation of dose, as growth disorders resulting from specific genetic variants necessitate early and higher dosage of growth hormone therapy. An accurate diagnosis is also essential before starting treatment, as hormone replacement in certain situations may expedite puberty, leading to the fusion of growth plates and cessation of longitudinal growth. We discovered novel candidate genetic variants, offering the physicians an opportunity to ascertain precise diagnosis. This will reduce the diagnostic odyssey and allow for the development of personalized treatment strategies.

Date of Award	2025
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences