スミス・マギニス症候群

A variety of genomic rearrangement mechanisms contribute to copy number variations at the 17p11.2 locus driven in part by its complex genomic architecture which is characterized by low copy repeats (LCRs) and other repetitive elements. These copy number variants are primarily mediated by nonallelic homologous recombination (NAHR) leading to recurrent tandem duplications and reciprocal deletions of the genomic interval mapping between the repeats. Two notable neurodevelopmental genomic disorders: Potocki-Lupski Syndrome (PTLS; MIM: 610883) and Smith-Magenis Syndrome (SMS; MIM: 182290) are driven by LCRs that undergo NAHR between the directly oriented repeats causing a duplication (PTLS) or deletion (SMS) encompassing the dosage-sensitive gene RAI1. We observed that other uncommon gains of varying sizes and extent at the 17p11.2 locus, which do not include the RAI1 gene, could be found in patients ascertained with a neurodevelopmental delay (NDD) phenotype. We ascertained 15 individuals from 11 families with copy number gains at the 17p11.2 locus not encompassing the driver gene-RAI1; such individuals manifested a broad spectrum of neurodevelopmental phenotypes. To validate our genomic findings, investigate DNA rearrangement mechanism(s), and refine our understanding at the breakpoint junctions, we performed a combination of high-resolution array CGH (n = 15), short-read whole-genome sequencing (sr-GS, n = 4), long-read GS (lr-GS; ONT; n = 4 and PacBio HiFi; n = 4), and breakpoint junctional analysis on this subset. Phenotypes in each individual were systematically studied. The phenotypes noted in these 15 individuals from 11 families primarily included developmental delay, intellectual disability, and behavioral problems. The genomic variations found in these 11 families included simple copy number gains (n = 7), higher order amplifications (n = 2), and complex genomic rearrangements (n = 2) at the 17p11.2 locus, surrounding the RAI1 gene and not encompassing it. Individuals from 4/11 families carried inherited variants. Identification of such rearrangement gains at the 17p11.2 locus that do not include the driver gene RAI1 and yet research subjects still exhibit neurodevelopmental phenotypes creates an opportunity to (i) dissect the gene(s) and genetic mechanisms that might contribute to phenotypic variability at the PTLS locus and (ii) uncover previously unrecognized genes or disease pathways and mechanisms.

Smith-Magenis syndrome (SMS) is a rare multisystem genetic disorder caused by a 17p11.2 microdeletion or pathogenic variants in the retinoic acid-induced 1 (RAI1) gene. It is characterized by developmental delay, distinctive craniofacial features, behavioral dysregulation, and inverted sleep-wake rhythm. Because early clinical findings are often nonspecific, diagnosis is frequently delayed, and patients may initially present to child psychiatry services with behavioral complaints. We report a 5-year-old girl referred for hyperactivity, severe circadian sleep disturbance with recurrent nocturnal awakenings, self-injurious behaviors, sensory-seeking behaviors, and developmental delay. Comprehensive psychiatric, developmental, neurological, physical, and genetic evaluations revealed a 17p11.2 microdeletion involving both RAI1 and folliculin (FLCN). The diagnosis of SMS was confirmed, and the involvement of FLCN indicated additional potential long-term medical risks. This case underscores the importance of considering genetic etiologies in children presenting with severe behavioral dysregulation and sleep problems and highlights the critical role of comprehensive genetic assessment in guiding diagnosis, management, and long-term follow-up.

Human brain development proceeds on an unusually long timeline relative to other species, a feature that is thought to foster advanced cognitive abilities. Retinoic Acid Induced 1 ( RAI1 ) gene encodes a nucleosome-binding protein haploinsufficient in Smith-Magenis Syndrome (SMS), a neurodevelopmental disorder characterized by cognitive impairment with autistic features. However, the role of RAI1 in human neurodevelopment remains unexplored experimentally. Here, we generated isogenic heterozygous and homozygous RAI1 loss-of-function human embryonic stem cell lines and interrogated the roles of RAI1 in neurodevelopmental gene regulation. A longitudinal transcriptome analysis during in vitro cortical development revealed that RAI1 deficiency accelerates developmental gene expression progression, including the precocious induction of synaptic genes. Single-cell RNA-seq analysis revealed that RAI1- deficient neuroprogenitors acquire a transient mesoderm-like gene expression signature followed by pro-neuronal maturation gene expression in postmitotic neurons. Unexpectedly, the developmental acceleration signature was exacerbated during NGN2-induced excitatory neuron differentiation, suggesting functional interplay between RAI1 and NGN2-driven programs. Together, these results identify RAI1 as a suppressor of the mesodermal lineage program and as a novel brake that slows the tempo of human neurodevelopmental gene expression.

Smith-Magenis syndrome (SMS) is caused by a deletion in the 17p11.2 region or abnormalities in the RAI1 gene. Clinically, it is characterized by distinctive facial features, sleep disturbances, and neurobehavioral traits such as self-injurious behaviors and developmental delays. It may also be accompanied by ophthalmologic, ear, nose, and throat (ENT), and cardiovascular abnormalities. The prevalence of cleft lip and palate in SMS is reported to range from 0% to 25%; however, there are no detailed reports on speech therapy or speech evaluations following surgery in such patients. Given the significant individual variability in developmental delays among patients with SMS, careful consideration is necessary when determining surgical indications for cleft palate. We conducted regular language assessments, including evaluations of mental development, with a speech therapist, and determined that the patient was a candidate for cleft palate surgery when pre-linguistic speech with meaningful elements was confirmed. Herein, we report a case of SMS in which palatoplasty was performed.

Smith-Magenis syndrome (SMS) is a rare neurodevelopmental disorder characterized by intellectual disability, behavioral dysregulation, and hyperphagia-driven obesity. While dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated efficacy in the general population, their use in patients with SMS has not been described. We report the case of a 31-year-old woman with SMS (17p11.2 deletion) treated with tirzepatide, a dual GIP/GLP-1 receptor agonist. The patient presented with lifelong obesity (body mass index [BMI] 32.0-32.9 kg/m2 in adulthood) and aggressive behaviors refractory to standard management. Following initiation of tirzepatide, titrated to 5 mg weekly, she achieved 9.4% weight loss (7.3 kg) over 10 months, along with improvement in fasting glucose levels. Concurrently, caregivers reported notable behavioral improvements, including reduced food-seeking behavior and impulsivity. Quantitative analysis demonstrated a significant reduction in aggression. The treatment was well tolerated. This case suggests that tirzepatide may represent a promising therapeutic option for SMS, targeting both metabolic and central nervous system pathways involved in its phenotype.