Targeted Gene Sequencing, Bone Health, and Body Composition in Cornelia de Lange Syndrome

Ángel Matute-Llorente,Feliciano Ramos,José A Casajus,María Arnedo,Elena Llorente,Luis A Moreno,Ariadna Ayerza-Casas,Laura Trujillano,Juan José Puente-Lanzarote,Ángela Ascaso,Juan Pié,Beatriz Puisac,Gloria Bueno-Lozano,Ana Latorre-Pellicer

doi:10.3390/app11020710

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/m2, 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.

Highlights

Brachmann de Lange syndrome and Cornelia de Lange syndrome (CdLS) were first described by Brachmann de Lange in 1916 [1] and Cornelia de Lange in 1933, respectively [2].Advancement in scientific knowledge was rather scarce during the following decades, until the 2000s, when research on Cornelia de Lange Syndrome (CdLS) grew exponentially [3,4,5,6]
All individuals were subjected to molecular analysis using a custom targeted gene panel consisting of 35 CdLS-related genes via deep sequencing analysis based on Ion Chef and Ion S5 XL Systems (Thermo Fisher Scientific), as described previously [23], including NIPBL, SMC1A, SMC3, RAD21, HDAC8, BRD4, ANKRD11, and MAU2
Deep sequencing for a custom target gene panel consisting of 35 genes related to CdLS discovered causative genetic variants in NIPBL

Summary

Introduction

Brachmann de Lange syndrome and Cornelia de Lange syndrome (CdLS) were first described by Brachmann de Lange in 1916 [1] and Cornelia de Lange in 1933, respectively [2].Advancement in scientific knowledge was rather scarce during the following decades, until the 2000s, when research on CdLS grew exponentially [3,4,5,6]. Brachmann de Lange syndrome and Cornelia de Lange syndrome (CdLS) were first described by Brachmann de Lange in 1916 [1] and Cornelia de Lange in 1933, respectively [2]. Jackson et al [7] reported that CdLS was slightly more common in females, but it affects men and women . It has been estimated the prevalence of CdLS is 1 case per 10,000–300,000 live births [3]. 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

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