A massive British study has discovered and diagnosed around 60 new rare genetic disorders – including the little-known Turnpenny Fry syndrome – after more than 13 500 families across the UK and Ireland were recruited as participants over 10 years.
The Deciphering Developmental Disorders (DDD) study specialises in analysing genetic code, with children and parents having their DNA analysed in their hunt for a diagnosis that can give families answers and lead to better care.
The Independent reports that all of the families had children with severe developmental disorders, undiagnosed despite prior testing through their national health services.
While the disorders are rare, the thousands of different genetic disorders taken collectively affect one in every 17 people in the country.
So far, researchers have been able to provide genetic diagnoses for around 5 500 children, but the search is still ongoing.
Among them is two-year-old Sofia Brogden, who was recruited to the DDD study and received a diagnosis when she was just one-month-old, while still in neonatal care.
She was diagnosed with Turnpenny-Fry syndrome, a rare genetic condition that causes learning difficulties, impaired growth and distinctive facial features that include a large forehead and sparse hair. Other common issues include feeding problems, severe constipation, as well as issues in the brain, heart and bones.
Turnpenny-Fry syndrome is caused by mutations in the PCGF2 gene.
Sofia, who lives with her parents Dasha and Carl in Oxfordshire, was born five weeks early and spent nearly three months at the neonatal care unit at John Radcliffe Hospital in Oxford.
Her mother said having an early diagnosis helped her understand what to expect. She said: “We were given a leaflet based on the experiences of other families, and through that, we knew she would need physiotherapy and occupational therapy. We learned that Sofia may have heart conditions, and a heart scan revealed that she needed surgery.
“She had a heart operation at two-months-old, and after that, she really started to make good progress, and we were able to take her home from the hospital.”
In the study, the genomes of the children and their parents were sequenced by The Wellcome Sanger Institute.
The findings, published in The New England Journal of Medicine, showed around three-quarters of the conditions were caused by spontaneous mutations not inherited from either parent.
Lead author Caroline Wright, professor of Genomic Medicine at the University of Exeter, said: “We found thousands of diagnoses in more than 800 known conditions, and the study itself also discovered around 60 new conditions. These included conditions caused by rare changes in genes such as ADNP, POGZ, DDX3X, PURA and many others.
“Getting the right diagnosis is absolutely critical for families with rare conditions, which collectively affect around one in 17 people. Most are genetic and can be diagnosed using the same genomic sequencing technology.
“The families in our study were desperate for answers, which can make a huge difference to clinical management and quality of life. We worked with hundreds of clinicians and scientists, as well as thousands of patients to try to find those answers.”
Study details
Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland
Caroline Wright, Patrick Campbell, Ruth Eberhardt, Stuart Aitken, Daniel Perrett, Simon Brent, Petr Danecek, Eugene Gardner, V. Kartik Chundru, Sarah Lindsay, Katrina Andrews, Juliet Hampstead, et al., for the DDD Study*
Published in The New England Journal of Medicine on 12 April 2023
Abstract
Background
Paediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits.
Methods
We conducted a large-scale sequencing study involving more than 13 500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardised phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis.
Results
A total of 13 449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent–offspring trio and 2.5 variants per singleton proband. With the use of clinical and computational approaches to variant classification, a diagnosis was made in approximately 41% of probands (5502 of 13 449), of whom 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13 449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent–offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks’ gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78).
Conclusions
Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis.
PCGF2 related syndrome QFN
NEJM article – Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland (Open access)
See more from MedicalBrief archives:
98% of rare diseases estimated to go undiagnosed in SA — advocacy group
UK to begin genome testing on 100 000 UK infants
Study queries usefulness of genome sequencing in primary care