# Targeted Gene Sequencing, Bone Health, and Body Composition in Cornelia de Lange Syndrome
## 4 Discussion  
As far as we know, this is the first study to assess bone health, body composition, and serum bone biomarkers in a sample of individuals with CdLS. Furthermore, deep sequencing for a custom target gene panel consisting of 35 genes related to CdLS discovered causative genetic variants in NIPBL. Therefore, this study will provide useful information for doctors, researchers, and therapists working with them. First, our sample consisted of children, adolescents, and adults, which can provide some information on the different evolutionary stages throughout the lives of people with CdLS. Although nine individuals may seem like a somewhat small number, our sample is quite similar to that of a study carried out by [PERSON] et al., in which 14 adults with CdLS were evaluated by DXA [3]. Moreover, it is important to underline that the assessment of body composition by DXA in individuals with CdLS is challenging. They must be motionless for the necessary exploration time. It is also complicated by the intellectual disability they have and the gastroesophageal reflux that occurs in the supine position. Previous studies described slow growth of CdLS individuals based on growth curves [3; 35]. On the one hand, some adolescents with CdLS might be underweight; on the other hand, adolescents with CdLS can became overweight and develop obesity, which can be induced by high-calorie meals along with low levels of physical activity or psychotherapeutic treatment options [3]. Along this line, other studies [7; 21] reported that between 18 and 30% of adolescents and adults with CdLS were overweight by BMI. BMI might not be accurate, because it could be masking important health-related body composition issues. Lean mass in growing individuals is related to growth as well as size. Thus, performing a more comprehensive body composition assessment with DXA allowed us to use other indices such as FMI and LMI. These variables improve on BMI by allowing for an independent assessment of fat and lean body mass. In addition, the ability to assess FMI and LMI independently and simultaneously is especially useful for children with chronic diseases [30]. Although seven out of nine individuals with CdLS had body fat percentages higher than 30%, despite some being classified as underweight according to BMI, only one individual was classified as having high adiposity by BMI. In the remaining sample, five individuals were classified as having normal adiposity, and three as having low adiposity by FMI. Focusing on lean mass, seven out of nine individuals were classified as having low levels of lean body mass by LMI. These findings are especially important in CdLS individuals, because they might show that fat and lean body mass may be affected differently, and a \"normal\" BMI may conceal deficits in lean mass, as happened for participant III (cachetic obesity) [36]. Moreover, three individuals (VI, VII, and VIII) had low lean body mass and low adiposity, and at least two of them could be classified as sarcopenia [37, 38]. This finding makes it reasonable to suppose that individuals with CdLS have low levels of lean mass in addition to slow growth and proportionate small stature [35]. Taking all of these factors into account--low levels of physical activity, low body weight, and low lean mass--according to [PERSON]'s mechanostat theory [39], even the youngest individuals with CdLS would be expected to have low bone mass. In the present study, using DXA to measure aBMD, we show that two out of nine individuals had a TBLH aBMD Z-score less than 2.0 SD. Thus, they had low bone mineral mass according to the 2019 official Pediatric Positions of the International Society for Clinical Densitometry (ISCD) [40]. This document indicates that in children with short stature or growth delay, aBMD results should be adjusted by height Z-scores. In addition, the diagnosis of osteoporosis in children and adolescents should be made based on densitometry and the presence of a clinically significant fracture history [40].