Large-scale evaluation of outcomes after a genetic diagnosis in children with severe developmental disorders

Abstract

Purpose: We sought to evaluate outcomes for clinical management after a genetic diagnosis from the Deciphering Developmental Disorders study.

Methods: Individuals in the Deciphering Developmental Disorders study who had a pathogenic/likely pathogenic genotype in the DECIPHER database were selected for inclusion (n = 5010). Clinical notes from regional clinical genetics services notes were reviewed to assess predefined clinical outcomes relating to interventions, prenatal choices, and information provision.

Results: Outcomes were recorded for 4237 diagnosed probands (85% of those eligible) from all 24 recruiting centers across the United Kingdom and Ireland. Clinical management was reported to have changed in 28% of affected individuals. Where individual-level interventions were recorded, additional diagnostic or screening tests were started in 903 (21%) probands through referral to a range of different clinical specialties, and stopped or avoided in a further 26 (0.6%). Disease-specific treatment was started in 85 (2%) probands, including seizure-control medications and dietary supplements, and contra-indicated medications were stopped or avoided in a further 20 (0.5%). The option of prenatal/preimplantation genetic testing was discussed with 1204 (28%) families, despite the relatively advanced age of the parents at the time of diagnosis. Importantly, condition-specific information or literature was given to 3214 (76%) families, and 880 (21%) were involved in family support groups. In the most common condition (KBG syndrome; 79 [2%] probands), clinical interventions only partially reflected the temporal development of phenotypes, highlighting the importance of consensus management guidelines and patient support groups.

Conclusion: Our results underscore the importance of achieving a clinico-molecular diagnosis to ensure timely onward referral of patients, enabling appropriate care and anticipatory surveillance, and for accessing relevant patient support groups.

Keywords: Clinical audit; Developmental disorders; Diagnosis; Genomic medicine; Treatment.

Figure 1

Summary of diagnosed DDD probands per center. Number of diagnosed Deciphering Developmental Disorders probands included in study (left) and percentage with interventions (treatment or testing; right) separated by the 24 Regional Genetic Services across the UK and Ireland. Black dotted line = mean across study.

Figure 2

Time to result and age of probands and parents at the point of diagnosis. Green, prenatal testing discussed or performed; PGT, preimplantation genetic testing; PND, prenatal diagnosis; red, no record of prenatal testing being discussed with the family.

Figure 3

Flowchart summarizing individual-level outcomes following a genetic diagnosis in the DDD study. Richer data collected using a mixture of controlled vocabulary and free text (see Supplemental Material). Individuals who experienced more than 1 outcome are included multiple times (ie, in all relevant boxes). ∗Some probands had >1 test initiated as a result of their diagnosis. PGT, preimplantation genetic test; PND, prenatal diagnosis.

Figure 4

Quasi-natural history of disease and summary of interventions for DDD probands diagnosed with the same condition. A-C. (A) ANKRD11, (B) CTNNB1, and (C) NSD1. Top panel—heatmap of phenotypes grouped by system and age; middle panel—heatmap of interventions grouped by age; bottom panel—histogram of number of probands in each group based on age at recruitment.