Identification of the Genetic Aetiology in a Cohort of Patients with Disorders of Sexual Development (DSD): diagnostic yield of Next Generation Sequencing (NSG).

CORREA BRITO LOURDES; SCAGLIA P; ESNAOLA AZCOITI, MARÍA; IZQUIERDO, AGUSTÍN; CASALI BARBARA; CASTRO S; JIMENA LOPEZ DACAL; SUCO SOFIA; BRUNELLO F; GRINSPON R; MARIA G. ROPELATO

Mar del Plata

Congreso; LXVIII Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2023

SAIC

In patients with DSD, an aetiologic diagnosis may not be reached even after deep phenotyping, i.e. clinical, hormonal and imaging assessment. The application of of NGS technology is promising in ascertaining the genetic diagnosis in suspected DSD. Our aim was to determine the diagnostic yield of NGS studies to establish the aetiologic diagnosis in a cohort of patients with DSD.We performed a cross-sectional study including patients with DSD in whom an aetiologic diagnosis had not been reached after phenotypic characterisation. Patients with chromosomal DSD were excluded. Patients and/or parents consented to participate. NGS data from targeted gene panel sequencing (Agilent or Twist) or Whole Exome Sequencing (WES) were processed by in house bioinformatic pipeline. Variant filtering and prioritisation were performed using B_platform (Bitgenia). Copy Number Variants (CNVs) were screened using DECoN. The variants were classified according to their potential pathogenicity using the ACMG/AMP guidelines and following the SVI WG recommendations.A molecular diagnosis was obtained in 7 of the 22 included patients. Five of them, who presented non-syndromic DSD, had (likely) pathogenic variants in AR, HSD17B3, NR5A1 or SRD5A2. A novel MYRF variant was identified in 1 patient with syndromic DSD, allowing us to identify a clinically inapparent congenital heart defect by reverse phenotyping. A clinically relevant deletion involving 40 genes (2,6 Mb in 3q27.1-3q27.2) was found in another patient with syndromic DSD.In conclusion, the diagnostic yield of NGS studies was 32% in patients with DSD in whom an aetiologic diagnosis had not been reached after deep phenotyping. Furthermore, reverse phenotyping allowed the identification of a clinically inapparent congenital heart defect in one case.