{"doi":"10.1002/ajmg.a.62380","title":"Possible underreporting of pathogenic variants in <scp> <i>RAI1</i> </scp> causing <scp>Smith–Magenis</scp> syndrome","abstract":"Smith–Magenis syndrome (SMS; OMIM #182290, *607642) is a rare genetic neurodevelopmental disorder, estimated to affect 1:15,000–25,000 live births (Elsea & Girirajan, 2008; Greenberg et al., 1991). In the absence of prevalence studies, this estimate is however very approximate, and is thought to be closer to 1:15,000 due to underdiagnosis of the condition (Elsea & Girirajan, 2008). SMS is associated with multiple manifestations including congenital malformations (mainly of the heart and kidneys), intellectual disability, severe sleep disturbances, behavioral problems such as self-injurious and aggressive behaviors, hypercholesterolemia, and overweight and obesity of variable severity (Elsea & Girirajan, 2008). SMS is caused by a 17p11.2 deletion or a pathogenic variant in the retinoic acid-induced gene 1 (RAI1) located within this chromosomal region (Slager et al., 2003). Previous studies have reported that approximately 90% of the patients have a 17p11.2 deletion. Of these, ~70% have a large and common deletion of 3.7 Mb, with the remaining 30% showing smaller or larger deletions ranging from 1.5 to 9 Mb (Edelman et al., 2007; Elsea & Girirajan, 2008; Finucane et al., 2021). Most of the SMS manifestations are thought to be the result of RAI1 haploinsufficiency and 10% of the patients with SMS are reported to have a pathogenic variant within RAI1 and no 17p11.2 deletion. Here, based on findings in a large SMS cohort, we propose that pathogenic variants in RAI1 causing SMS may be underreported. We reviewed available medical records from patients with a molecular diagnosis of SMS who visited the Dutch clinic for patients with SMS at 's Heeren Loo between 2002 and 2021. Originally a monodisciplinary medical clinic focusing on the treatment of sleep disorders (Spruyt et al., 2016), it has evolved to a multidisciplinary expert center providing patient-centered care to patients and their families by health-care experts from many specialties, including but not limited to intellectual disability medicine, psychology, speech–language pathology, dietetics and nutrition, and sensory integration therapy. We recorded information on ascertainment, demographic variables, and genetics, including age at last assessment, sex, age at genetic confirmation of the diagnosis, and details of the 17p11.2 deletion or RAI1 variant when available. A waiver for formal approval was obtained from the Institutional Review Board of Amsterdam UMC, the Netherlands (#W20_098). To determine differences in molecular diagnostic age and sex between patients with a 17p11.2 deletion and patients with a RAI1 variant, we used Mann–Whitney U and Fisher's exact tests, respectively. These analyses were two-tailed, with statistical significance defined as p < 0.05, using IBM SPSS software (Statistics 25; SPSS, Inc, Chicago, IL). Patients were referred to our clinic through four main sources, from most to least frequent: pediatrics, family medicine, medical genetics, and intellectual disability medicine. The sample comprised 87 patients with SMS aged 0–45 years (41 females, 47%) at last assessment. Sixty-seven patients (77%) had a 17p11.2 deletion, of whom in 30 (45%) the deletion size was known: 23 (77%) had a common deletion of ~3.7 Mb, 5 (17%) a smaller, and 2 (7%) a larger deletion. Two patients (2%), both with a 17p11.2 deletion, had an additional genetic finding of clinical relevance: myotonic dystrophy type 1 and compound heterozygous variants in the phenylalanine hydroxylase gene associated with a mild phenylketonuria phenotype, respectively. Twenty patients (23%) had a pathogenic RAI1 variant: 15 (83%) a frameshift and 3 (17%) a nonsense variant. In two patients, details about the variant were unknown. There were no statistically significant differences in sex between 17p11.2 patients (29 females; 43%) and those with a RAI1 variant (12 females, 60%, p = 0.21). The median age at genetic confirmation of the diagnosis was statistically significant higher in the patient","journal":"American Journal of Medical Genetics Part A","year":2021,"id":179450,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":727799,"name":"Cathelijne C. Linders","orcid":null,"position":1,"is_corresponding":false},{"id":727800,"name":"Sterre H. Tromp","orcid":null,"position":2,"is_corresponding":false},{"id":433623,"name":"Marie‐José H. van den Boogaard","orcid":"0000-0002-3100-9337","position":3,"is_corresponding":false},{"id":726980,"name":"Agnies M. van Eeghen","orcid":"0000-0001-8149-8645","position":4,"is_corresponding":false},{"id":263901,"name":"Erik Boot","orcid":"0000-0002-0593-1539","position":0,"is_corresponding":true}],"reference_count":13,"raw_metadata":null,"created_at":"2026-07-18T23:47:48.974996Z","pmid":"34089220","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}