Intellectual disability affects 1% to 3% of the global population, occurs more frequently in males than females, and has higher prevalence in low- and middle-income countries than in high-income countries.1 The intellectual disability spectrum varies widely from mild to severe, and may be non-syndromic, or associated with additional neurological features or additional organ system involvement such as congenital anomalies, hearing or visual impairment, or epilepsy. Identifiable causes of intellectual disability may be environmental (infectious, teratogenic, intraventricular hemorrhage associated with preterm birth, etc.) or genetic (chromosomal aneuploidy, copy number variants or structural anomalies, monogenic X-linked, recessive, or de novo autosomal conditions, mitochondrial or imprinted disorders). The genetic diagnostic tools available to clinicians have evolved over the past two decades from fragile X and karyotyping to next-generation sequencing allowing for testing panels of hundreds of genes, up to exome or genome sequencing. Recently, exome or genome sequencing have come into the mainstream as first-line genetic testing for most children with developmental delay/intellectual disability or multiple congenital anomalies.2, 3 Venetvaara et al.4 report a population-based retrospective study of a cohort of 959 children with intellectual disability seen between 2017 and 2021 at an academic hospital in Finland. Since the genetic testing occurred over a 22-year period, a wide range of standard genetic testing was performed with chromosomal microarray, fragile X, exome sequencing, and karyotype being the most common with an overall diagnostic yield of 437 out of 959 (46%) patients. In this real-world study, the most important insights came from clinical characterization by confirmation through records review of: the diagnosis and severity of intellectual disability, assessment for additional significant clinical features, and assessment for preterm birth and environmental causes of intellectual disability. The authors' detailed review showed that chromosomal anomalies were enriched in patients with intellectual disability and congenital heart disease, and monogenic variants were more common in patients with intellectual disability and epilepsy or ophthalmological abnormalities. Furthermore, associated conditions resulting in congenital heart disease, visual impairment, hearing impairment, autism spectrum disorder, or epilepsy were more common with more severe intellectual disability. This suggests that patients with moderate or severe intellectual disability may need screening for certain medical conditions at the time of diagnosis, and in some cases, further evaluation for comorbidities during follow-up. Other important lessons from the present study for clinical practice were that 90 out of 959 (9%) patients had non-genetic causes of intellectual disability, most related to preterm birth or hemorrhage, and that 18 out of 165 (11%) individuals were diagnosed with a potentially treatable genetic metabolic conditions. Not all insights gained from this study are likely to apply to other populations. For example, in this cohort consisting of almost entirely patients of Finnish ancestry, there was a substantial number of patients with autosomal recessive metabolic diseases with likely pathogenic/pathogenic founder variants enriched in persons of Finnish heritage. The ability to identify a cause of intellectual disability for almost half of children with current technology is remarkable progress. Understanding of the causes for the remaining half is an area of active investigation and future research, with the promise of additional discoveries through long-read sequencing, methylation studies, genome sequencing, RNA sequencing and transcriptomics, metabolomics, and the integration of multi-omic data.5 Not required.
Fuki M. Hisama (Thu,) studied this question.