Challenges and suggested improvements for identification, monitoring, and treatment of familial HMs
| Detection and classification | Population- and cohort-specific frequency of FHM gene defects |
| Comprehensive personal and family history for all patients at diagnosis, with urgent attention if SCT is needed | |
| Comprehensive and integrative genomics screening: capturing indels and noncoding variants, as well as frank coding variants | |
| Appropriate germline reference material for interpretation of tumor molecular screening results (hair bulbs, MSC, fibroblasts) | |
| Continued development and correct application of expert panel gene-specific ACMG guidelines (eg, ClinGen RUNX1 rules) | |
| Appropriate expert review (MDT) of variants before clinical notification: focus on variants of uncertain significance or variants with existing classification discordance | |
| Risk assessment and monitoring | Gene-specific longitudinal cohort studies, including comprehensive phenotype screening and monitoring protocols |
| Comprehensive phenotyping: age of onset in family, including evidence of anticipation, history of infections (HSC stress), partial penetrance, asymptomatic carriers | |
| Cohort aggregation of genomics data (eg, RUNX1db) for analysis of germline mutation–specific associations, acquired mutations in blood/marrow, germline modifiers, epigenetics and gene expression (eg, allelic imbalance) | |
| High-depth molecular monitoring of blood/marrow from asymptomatic carriers for progression mutations | |
| New and effective treatments | Mutation-specific in vivo and in vitro systems for disease modeling, including progression, drug screening, and preclinical studies |
| Premalignant interventions (eg, ameliorate HSC stress, target early somatic drivers) | |
| International clinical trial consortia for rapid testing of new therapeutic options for rare FHM disorders |
| Detection and classification | Population- and cohort-specific frequency of FHM gene defects |
| Comprehensive personal and family history for all patients at diagnosis, with urgent attention if SCT is needed | |
| Comprehensive and integrative genomics screening: capturing indels and noncoding variants, as well as frank coding variants | |
| Appropriate germline reference material for interpretation of tumor molecular screening results (hair bulbs, MSC, fibroblasts) | |
| Continued development and correct application of expert panel gene-specific ACMG guidelines (eg, ClinGen RUNX1 rules) | |
| Appropriate expert review (MDT) of variants before clinical notification: focus on variants of uncertain significance or variants with existing classification discordance | |
| Risk assessment and monitoring | Gene-specific longitudinal cohort studies, including comprehensive phenotype screening and monitoring protocols |
| Comprehensive phenotyping: age of onset in family, including evidence of anticipation, history of infections (HSC stress), partial penetrance, asymptomatic carriers | |
| Cohort aggregation of genomics data (eg, RUNX1db) for analysis of germline mutation–specific associations, acquired mutations in blood/marrow, germline modifiers, epigenetics and gene expression (eg, allelic imbalance) | |
| High-depth molecular monitoring of blood/marrow from asymptomatic carriers for progression mutations | |
| New and effective treatments | Mutation-specific in vivo and in vitro systems for disease modeling, including progression, drug screening, and preclinical studies |
| Premalignant interventions (eg, ameliorate HSC stress, target early somatic drivers) | |
| International clinical trial consortia for rapid testing of new therapeutic options for rare FHM disorders |
ACMG, American College of Medical Genetics and Genomics; MDT, multidisciplinary team; MSC, mesenchymal stem cell.