Genome sequencing improves diagnoses in Belgian developmental-disorder study

Genome sequencing produced more diagnoses than standard testing in a nationwide Belgian trial involving 567 people with unexplained developmental disorders, according to research reported by Springer Nature’s Genome Medicine. The advantage was clearest before adjustments were made for differences between the groups and their sex distribution.

The study brought together all human genetics centres in Belgium. Participants were assigned to receive either genome sequencing (GS) or the standard of care (SoC). The conventional approach combined exome sequencing (ES) with chromosomal microarray analysis, or used shallow genome sequencing.

Among the 284 participants assigned to GS, a genetic diagnosis was reached for 113, representing 39.8% of the group. In the standard-care arm, 85 of 283 participants received a diagnosis, or 30%. The difference was statistically significant, with GS identifying 8.7 percentage points more cases involving single-nucleotide variants and small insertions or deletions.

The trial was prospective and randomised, although its registration was retrospective. Its results point to a possible benefit from using genome sequencing earlier in the diagnostic process for people whose developmental difficulties have no known explanation.

What genome sequencing added

Genome sequencing examines genetic material across the genome, while exome sequencing focuses on the protein-coding regions. In this study, the broader test did more than increase the number of diagnoses involving small genetic changes. It also found three potentially disease-causing variants outside coding regions, which the researchers described as non-coding variants.

Those findings matter because a test can miss a possible explanation when analysis is limited to regions traditionally considered most relevant to disease. The three non-coding findings did not account for the whole difference between the testing strategies, but they demonstrated an additional type of information available through GS.

The results also showed that the likelihood of finding a diagnosis differed substantially by sex. Across the two study groups combined, the diagnostic yield was 45.5% among females, compared with 28.5% among males. The study included 213 females and 354 males, and the difference was statistically significant.

Once the researchers adjusted for the unequal sex distribution and for analytical differences between the two study arms, the gap between GS and standard care narrowed to 7.3 percentage points. At that stage, the difference no longer met the study’s threshold for statistical significance, with a reported p value of 0.069.

Inherited changes were important too

The analysis examined whether genetic changes had arisen newly in the affected person or had been inherited. Variants that were not present in either parent, known as de novo variants, were identified in 23.6% of participants.

Inherited variants also made a meaningful contribution. Changes in genes linked to autosomal dominant conditions accounted for 3.9% of diagnoses. This was greater than the contribution from X-linked variants, at 1.9%, and close to the contribution from autosomal recessive variants, at 4.1%.

The comparison is relevant to how genomic data are assessed. The findings indicate that inherited changes associated with autosomal dominant disorders should remain part of the search, rather than analysis concentrating mainly on newly arising variants or on other inheritance patterns.

Implications for genetic diagnosis

Exome and genome sequencing are already recommended as first- or second-tier molecular tests for people with developmental disorders. The continuing question has been whether genome sequencing offers enough additional clinical value to justify using it in place of, or ahead of, established combinations of tests.

In the Belgian trial, GS generated the higher unadjusted diagnostic yield in a decentralised hospital setting and among a cohort described as well characterised. That setting gives the comparison practical relevance beyond a single specialist centre, because the participants were drawn from the country’s network of human genetics services.

The study does not remove every uncertainty. The adjusted comparison was less conclusive than the initial result, reflecting the influence of sex distribution and differences in how the two strategies were analysed. Even so, the overall findings reported by Springer Nature support genome sequencing as a strong diagnostic option for unexplained developmental disorders and underline the need to assess both new and inherited genetic variants.