Gaps in the phenotype descriptions of ultra-rare genetic conditions: review and multicenter consensus reporting guidelines
medrxiv(2023)
摘要
Background Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-first ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear.
Methods We identified reports published from 2017-2021 in ten genetics journals of novel Mendelian disorders ascertained genotype-first. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries.
Results In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the six domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and “behavioural issues”, or about the type/nature of feeding problems. Follow-up reports (n=95) rarely addressed the limitations of the original reports. Reporting guidelines were developed for each domain.
Conclusion Phenotype information relevant to clinical management, genetic counseling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. Use of the proposed guidelines could improve phenotype reporting in the genomic era.
### Competing Interest Statement
D.B. has received research funds from MapLight Therapeutics. K.W. has consulted for Stoke Therapeutics. J.A.S.V. has served as a consultant for NoBias Therapeutics Inc. and has received speaker fees for Henry Stewart Talks Ltd. These relationships did not influence content of this manuscript but are disclosed for potential future considerations.The remaining authors declare no financial or non-financial competing interests.
### Funding Statement
This study was funded by (refer to manuscript draft for funding details).
### Author Declarations
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Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Ethics committee of The Hospital for Sick Children gave ethical approval for this work
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