# Targeted Gene Sequencing, Bone Health, and Body Composition in Cornelia de Lange Syndrome
###### Abstract  
The aim of this study was to evaluate bone health and body composition by dual-energy X-ray absorptiometry (DXA) in individuals with Cornelia de Lange Syndrome (CdLS). Overall, nine individuals with CdLS (five females, all Caucasian, aged 5-38 years) were assessed. Total body less head (TBLH) and lumbar spine (LS) scans were performed, and bone serum biomarkers were determined. Molecular analyses were carried out and clinical scores and skeletal features were assessed. Based on deep sequencing of a custom target gene panel, it was discovered that eight of the nine CdLS patients had potentially causative genetic variants in _NIPBL_. Fat and lean mass indices (FMI and LMI) were 3.4-11.1 and 8.4-17.0 kg/m\({}^{2}\), respectively. For TBLH areal bone mineral density (aBMD), after adjusting for height for age Z-score of children and adolescents, two individuals (an adolescent and an adult) had low BMD (aBMD Z-scores less than -2.0 SD). Calcium, phosphorus, 25-OH-vitamin D, parathyroid hormone, and alkaline phosphatase levels were 2.08-2.49 nmol/L, 2.10-3.75 nmol/L, 39.94-78.37 nmol/L, 23.4-80.3 pg/mL, and 43-203 IU/L, respectively. Individuals with CdLS might have normal adiposity and low levels of lean mass measured with DXA. Bone health in this population seems to be less of a concern during childhood and adolescence. However, they might be at risk for impaired bone health due to low aBMD in adulthood. C 2021 by the authors. Li-conseee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([[https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)]([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/))). the 2000s, when research on CdLS grew exponentially [3; 4; 5; 6]. [PERSON] et al. [7] reported that CdLS was slightly more common in females, but it affects men and women equally. It has been estimated the prevalence of CdLS is 1 case per 10,000-300,000 live births [3]. Therefore, CdLS is recognized as a rare disease. CdLS is a consequence of spontaneous mutations in genes of the cohesion protein complex. _NIPBL_ mutations are the most prevalent variants and occur in approximately 60-80% of cases [8; 9; 10; 11; 12; 13]. To date, new advances in genomic techniques are making it possible for clinicians to improve the diagnosis of mutations in the known CdLS genes (_SMC1A_, _SMC3_, _RAD21_, _BRD4_, _HDAC8_, _ANKRD11_, and _MAU2_) [14; 15; 16; 17; 18; 19], and other candidates are being proposed [20]. The CdLS phenotype is characterized as a spectrum because it includes individuals with the classic CdLS phenotypes (with scores \(\geq\)11 points), as well as individuals with nonclassic CdLS phenotypes (9-10 points), based on the first published international consensus on the diagnosis and management of CdLS [8]. Recent evidence [8] suggests that most people with CdLS present bone-related medical problems such as scoliosis or short stature. In addition, cardiovascular problems and intellectual disability, combined with limited physical activity [3] and restricted mobility, may harm the bone health and body composition of people with CdLS. However, the available scientific literature about body composition in these individuals is almost nonexistent. We found only two studies [7; 21] reporting that 18-30% of adolescents and adults with CdLS were overweight. Previous studies used body mass index (BMI) to determine overweight and obesity; however, using the fat mass index (FMI) and lean mass index (LMI) provides an improvement, because BMI cannot distinguish between fat mass and lean body mass [22]. As far as we know, when assessing body composition and bone health in children and adolescents with CdLS, there are no data published with more complex techniques such as dual-energy X-ray absorptiometry (DXA). However, low bone density was described in a sample of 12 adults with CdLS [3].