Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are reciprocal genomic disorders caused by deletions and duplications of the 17p11.2 chromosomal region, respectively. This study aimed to identify and validate DNA methylation episignatures specific to SMS and PTLS, and to investigate their reciprocal relationship and shared molecular features with other neurodevelopmental disorders. Genome-wide DNA methylation was analyzed in individuals with an SMS (n = 26) or PTLS (n = 27) phenotype associated with copy number variation, and SMS patients with RAI1 sequence variants using the Infinium EPIC array. Differentially methylated CpG sites were identified and used to develop support vector machine (SVM)-based classifiers, which demonstrated high sensitivity and specificity for both syndromes. The analysis revealed a mirror-like episignature, with SMS showing predominant hypomethylation and PTLS displaying hypermethylation at shared loci. Functional correlation with other neurodevelopmental disorders highlighted significant overlap with known episignatures, including those associated with MEF2C-related disorders. Notably, individuals with RAI1 sequence variants did not exhibit the same DNA methylation patterns, suggesting that the epigenetic alterations are primarily driven by copy number changes. These findings establish SMS and PTLS as distinct yet interconnected epigenetic entities, offering valuable diagnostic biomarkers and insights into the molecular pathophysiology of 17p11.2-associated neurodevelopmental disorders.

Potocki-Lupski syndrome (PTLS) is a rare genetic disorder, with an estimated prevalence of 1:25 000. Detection of a duplication at position 17p11.2 comprising the RAI1 gene establishes the diagnosis. Deletion of this same region is responsible for Smith-Magenis syndrome (SMS). Hitherto, the non-specific clinical features included psychomotor and growth retardation and multiple congenital anomalies. Our aim was to further delineate the clinical spectrum of PLTS. We gathered a series of 56 individuals carrying a 17p11.2 duplication, one of the largest reported to date. We collected detailed phenotypic data and established a phenotypic comparison with individuals already described in the literature. We corroborated the main clinical signs associated with PTLS and highlighted additional features present in a significant proportion in our series, such as intrauterine growth retardation or low birth weight, musculoskeletal and ophthalmological anomalies, and abnormalities of the skin appendages. In line with previous reports, behavioural disorders were frequently identified (23%). Yet unexpectedly, self-aggressive and hetero-aggressive behaviours, characteristic features of SMS, were found in a small number of individuals. Forty-six individuals harboured the recurrent duplication (85%), five had larger duplications (9%) and three had smaller duplications (6%). We did not identify inherited duplications when parental information was available (n=43). Our study refined the clinical features of PTLS and their relative frequencies. Our findings therefore contribute to improving management of people with PTLS. These open up new pathophysiological hypotheses involving RAI1 gene dosage of the genesis and control of behaviour, as well as new, more complex regulatory pathways.

Haploinsufficiency disorders are genetic diseases caused by reduced gene expression, leading to developmental, metabolic, and tumorigenic abnormalities. The dosage-sensitive Retinoic Acid Induced 1 (RAI1) gene, located within the 17p11.2 region, is central to the core features of Smith--Magenis syndrome (SMS) and Potocki--Lupski syndrome (PTLS), caused by the reciprocal microdeletions and microduplications of this region, respectively. SMS and PTLS present contrasting phenotypes. SMS is characterized by severe neurobehavioral manifestations, sleep disturbances, and metabolic abnormalities, and PTLS shows milder features. Here, we detail the molecular functions of RAI1 in its wild-type and haploinsufficiency conditions (RAI1+/-), as studied in animal and cellular models. RAI1 acts as a transcription factor critical for neurodevelopment and synaptic plasticity, a chromatin remodeler within the Histone 3 Lysine 4 (H3K4) writer complex, and a regulator of faulty 5'-capped pre-mRNA degradation. Alterations of RAI1 functions lead to synaptic scaling and transcriptional dysregulation in neural networks. This review highlights key molecular mechanisms of RAI1, elucidating its role in the interplay between genetics and phenotypic features and summarizes innovative therapeutic approaches for SMS. These data provide a foundation for potential therapeutic strategies targeting RAI1, its mRNA products, or downstream pathways.

Retinoic acid-induced 1 (RAI1) is a dosage-sensitive gene implicated in a range of rare neuropsychiatric diseases. This review provides a comprehensive overview of RAI1's role, integrating both clinical and basic research on Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) while also summarising research progress on its involvement in spinocerebellar ataxia (SCA), autism spectrum disorder (ASD), schizophrenia, bipolar disorder and major depression. A systematic review of the literature was conducted using PubMed and EMBASE, following the PRISMA guidelines, with the protocol registered in PROSPERO (CRD42023474165). A total of 99 eligible studies on RAI1 were included. We presented detailed characterisations of SMS and PTLS patients, emphasising the crucial role of RAI1 haploinsufficiency and overexpression in their pathogenesis. Additionally, we summarised research progress on RAI1 in SCA, ASD, schizophrenia, bipolar disorder and major depression. Integrating findings from animal studies, particularly those examining the regulatory mechanisms of RAI1 in critical phenotypes, such as body weight, sleep and epilepsy, underscores the precise regulation of RAI1 expression in maintaining various nervous system functions. Overall, this review contributes to the identification of RAI1-related neuropsychiatric diseases, with a particular emphasis on enhancing clinical diagnosis of SMS and PTLS in developing countries.

Variable copy number variations (CNVs) in the short arm of chromosome 17 are associated with many neurodevelopmental disorders, including Charcot-Marie-Tooth disease type 1A, Potocki-Lupski syndrome and Yuan-Harel-Lupski syndrome. Here we examined CNVs in two sporadic cases of developmental abnormalities, brain impairment and peripheral neuropathy. We identified novel duplications of approximately 14.1 Mb at 17p11.2-p13.1 (containing PMP22 and RAI1) and 17.6 Mb at 17p11.2-p13.3 (YWHAE, PAFAH1B and PMP22) in each patient. Both duplications were suggested to be produced by de novo mutations of paternal origin. This study suggests that CNVs at 17p should be examined in patients with peripheral neuropathy as well as developmental and brain abnormalities.