Reverse Phenotyping after Whole-Exome Sequencing in Children with Developmental Delay/Intellectual Disability-An Exception or a Necessity?

Nikola Ilic; Nina Maric; Ales Maver; Lluis Armengol; Ruzica Kravljanac; Jana Cirkovic; Jovana Krstic; Danijela Radivojevic; Sanja Cirkovic; Slavica Ostojic; Stasa Krasic; Aleksandra Paripovic; Vladislav Vukomanovic; Borut Peterlin; Gorica Maric; Adrijan Sarajlija

doi:10.3390/genes15060789

Reverse Phenotyping after Whole-Exome Sequencing in Children with Developmental Delay/Intellectual Disability-An Exception or a Necessity?

Genes (Basel). 2024 Jun 15;15(6):789. doi: 10.3390/genes15060789.

Authors

Nikola Ilic¹, Nina Maric², Ales Maver³, Lluis Armengol⁴, Ruzica Kravljanac^{5

6}, Jana Cirkovic¹, Jovana Krstic¹, Danijela Radivojevic⁷, Sanja Cirkovic⁷, Slavica Ostojic^{5

6}, Stasa Krasic⁸, Aleksandra Paripovic^{6

9}, Vladislav Vukomanovic^{6

8}, Borut Peterlin³, Gorica Maric¹⁰, Adrijan Sarajlija^{1

6}

Affiliations

¹ Clinical Genetics Outpatient Clinic, Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic", 11070 Belgrade, Serbia.
² Clinic for Children Diseases, University Clinical Center of the Republic of Srpska, Banja Luka 78000, Bosnia and Herzegovina.
³ Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.
⁴ CIBER en Epidemiología y Salud Pública (CIBERESP), Genes and Disease Program, Center for Genomic Regulation (CRG-UPF), 08003 Barcelona, Spain.
⁵ Department of Neurology, Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic", 11070 Belgrade, Serbia.
⁶ Department of Pediatrics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
⁷ Laboratory of Medical Genetics, Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic", 11070 Belgrade, Serbia.
⁸ Department of Cardiology, Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic", 11070 Belgrade, Serbia.
⁹ Department of Nephrology, Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic", 11070 Belgrade, Serbia.
¹⁰ Institute of Epidemiology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.

Abstract

This study delves into the diagnostic yield of whole-exome sequencing (WES) in pediatric patients presenting with developmental delay/intellectual disability (DD/ID), while also exploring the utility of Reverse Phenotyping (RP) in refining diagnoses. A cohort of 100 pediatric patients underwent WES, yielding a diagnosis in 66% of cases. Notably, RP played a significant role in cases with negative prior genetic testing, underscoring its significance in complex diagnostic scenarios. The study revealed a spectrum of genetic conditions contributing to DD/ID, illustrating the heterogeneity of etiological factors. Despite challenges, WES demonstrated effectiveness, particularly in cases with metabolic abnormalities. Reverse phenotyping was indicated in half of the patients with positive WES findings. Neural network models exhibited moderate-to-exceptional predictive abilities for aiding in patient selection for WES and RP. These findings emphasize the importance of employing comprehensive genetic approaches and RP in unraveling the genetic underpinnings of DD/ID, thereby facilitating personalized management and genetic counseling for affected individuals and families. This research contributes insights into the genetic landscape of DD/ID, enhancing our understanding and guiding clinical practice in this particular field of clinical genetics.

Keywords: developmental delay (DD); intellectual disability (ID); neural network analysis; reverse phenotyping (RP); whole-exome sequencing (WES).

MeSH terms

Adolescent
Child
Child, Preschool
Developmental Disabilities* / genetics
Exome Sequencing* / methods
Female
Genetic Testing / methods
Humans
Infant
Intellectual Disability* / genetics
Intellectual Disability* / pathology
Male
Phenotype*

Grants and funding

This research received no external funding.