Exploring an objective measure of overactivity in children with rare genetic syndromes.

BACKGROUND: Overactivity is prevalent in several rare genetic neurodevelopmental syndromes, including Smith-Magenis syndrome, Angelman syndrome, and tuberous sclerosis complex, although has been predominantly assessed using questionnaire techniques. Threats to the precision and validity of questionnaire data may undermine existing insights into this behaviour. Previous research indicates objective measures, namely actigraphy, can effectively differentiate non-overactive children from those with attention-deficit hyperactivity disorder. This study is the first to examine the sensitivity of actigraphy to overactivity across rare genetic syndromes associated with intellectual disability, through comparisons with typically-developing peers and questionnaire overactivity estimates. METHODS: A secondary analysis of actigraphy data and overactivity estimates from The Activity Questionnaire (TAQ) was conducted for children aged 4-15 years with Smith-Magenis syndrome (N=20), Angelman syndrome (N=26), tuberous sclerosis complex (N=16), and typically-developing children (N=61). Actigraphy data were summarized using the M10 non-parametric circadian rhythm variable, and 24-hour activity profiles were modelled via functional linear modelling. Associations between actigraphy data and TAQ overactivity estimates were explored. Differences in actigraphy-defined activity were also examined between syndrome and typically-developing groups, and between children with high and low TAQ overactivity scores within syndromes. RESULTS: M10 and TAQ overactivity scores were strongly positively correlated for children with Angelman syndrome and Smith-Magenis syndrome. M10 did not substantially differ between the syndrome and typically-developing groups. Higher early morning activity and lower evening activity was observed across all syndrome groups relative to typically-developing peers. High and low TAQ group comparisons revealed syndrome-specific profiles of overactivity, persisting throughout the day in Angelman syndrome, occurring during the early morning and early afternoon in Smith-Magenis syndrome, and manifesting briefly in the evening in tuberous sclerosis complex. DISCUSSION: These findings provide some support for the sensitivity of actigraphy to overactivity in children with rare genetic syndromes, and offer syndrome-specific temporal descriptions of overactivity. The findings advance existing descriptions of overactivity, provided by questionnaire techniques, in children with rare genetic syndromes and have implications for the measurement of overactivity. Future studies should examine the impact of syndrome-related characteristics on actigraphy-defined activity and overactivity estimates from actigraphy and questionnaire techniques.

Speech, Language, Hearing, and Otopathology Results From the International Smith-Magenis Syndrome Patient Registry.

PURPOSE: Smith-Magenis syndrome (SMS), a rare, genetically linked complex developmental disorder caused by a deletion or mutation within chromosome 17p11.2, is associated with delays in speech-language development, otopathology, and hearing loss, yet previous studies lack comprehensive descriptions of hearing and communication profiles. Here, analyses of patient registry data expand what is known about speech, language, hearing, and otopathology in SMS. METHOD: International speech-language and hearing registry survey data for 82 individuals with SMS were analyzed using descriptive and inferential statistics. Hearing loss, history of otitis media and pressure equalization (PE) tubes, communication mode, expressive/receptive language, and vocal quality were analyzed for all subjects and subjects grouped by age. Statistical methods included descriptive statistics and Pearson's chi-square tests of independence to test for differences between age groups for each variable of interest. Association analyses included Pearson's correlations. RESULTS: Hearing and otological analyses revealed that 35% of subjects had hearing loss, 66% had a history of otitis media, and 62% had received PE tubes. Speech-language analyses revealed that 60% of subjects communicated using speech, 79% began speaking words at/after 24 months of age, 92% combined words at/after 36 months, and 41% used sign language before speech. There was a significant association between the age that first words were spoken and the age that PE tubes were first placed. Communication strengths noted in more than 40% of subjects included social interest, humor, and memory for people, past events, and/or facts. CONCLUSIONS: Significant delays and impairment in speech-language were common, but the majority of those with SMS communicated using speech by age 6 years. Age was a significant factor for some aspects of hearing loss and communication. Neither hearing loss nor otitis media exacerbated language impairment. These results confirm and extend previous findings about the nature of speech, language, hearing, and otopathology in those with SMS.

Comparative analyses of the Smith-Magenis syndrome protein RAI1 in mice and common marmoset monkeys.

Retinoic acid-induced 1 (RAI1) encodes a transcriptional regulator critical for brain development and function. RAI1 haploinsufficiency in humans causes a syndromic autism spectrum disorder known as Smith-Magenis syndrome (SMS). The neuroanatomical distribution of RAI1 has not been quantitatively analyzed during the development of the prefrontal cortex, a brain region critical for cognitive function and social behaviors and commonly implicated in autism spectrum disorders, including SMS. Here, we performed comparative analyses to uncover the evolutionarily convergent and divergent expression profiles of RAI1 in major cell types during prefrontal cortex maturation in common marmoset monkeys (Callithrix jacchus) and mice (Mus musculus). We found that while RAI1 in both species is enriched in neurons, the percentage of excitatory neurons that express RAI1 is higher in newborn mice than in newborn marmosets. By contrast, RAI1 shows similar neural distribution in adult marmosets and adult mice. In marmosets, RAI1 is expressed in several primate-specific cell types, including intralaminar astrocytes and MEIS2-expressing prefrontal GABAergic neurons. At the molecular level, we discovered that RAI1 forms a protein complex with transcription factor 20 (TCF20), PHD finger protein 14 (PHF14), and high mobility group 20A (HMG20A) in the marmoset brain. In vitro assays in human cells revealed that TCF20 regulates RAI1 protein abundance. This work demonstrates that RAI1 expression and protein interactions are largely conserved but with some unique expression in primate-specific cells. The results also suggest that altered RAI1 abundance could contribute to disease features in disorders caused by TCF20 dosage imbalance.

Psychiatric and neurological manifestations in adults with Smith-Magenis syndrome: A scoping review.

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder caused by a 17p11.2 deletion or a pathogenic variant of the RAI1 gene, which lies within the 17p11.2 region. Various psychiatric and neurological disorders have been reported in SMS, with most literature focusing on children and adolescents. To provide an overview of the current knowledge on this topic in adults with SMS, we performed a comprehensive scoping review of the relevant literature. Our findings suggest that many manifestations that are common in childhood persist into adulthood. Neuropsychiatric manifestations in adults with SMS include intellectual disability, autism spectrum- and attention deficit hyperactivity disorder-related features, self-injurious and physical aggressive behaviors, sleep-wake disorders, and seizures. Findings of this review may facilitate optimization of management strategies in adults with SMS, and may guide future studies exploring late-onset psychiatric and neurological comorbidities in SMS.

Smith-Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling.

Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVHBDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.

A case of Smith-Magenis syndrome with skin manifestations caused by a novel locus mutation in the RAI1 gene.

We report the clinical features and genetic testing of a child with Smith-Magenis syndrome (SMS) to improve the understanding of this disease. The clinical data and molecular genetic test results of a child with SMS caused by a novel mutation in the retinoic acid-induced-1 (RAI1) gene were reviewed. A female patient aged 12 years and 9 months presented to the clinic because her mental and motor development was lagging behind that of her peers. The child had learning difficulties, poor motor coordination, temper tantrums, and self-injurious behaviors, such as skin scratching. She had a peculiar facial appearance, dry skin with scattered eczema, low hairline, wide forehead, flat face, collapsed nasal bridge, turned out upper lip, and deep palmar lines on the right hand through the palm. Wechsler's IQ test score was 48. Her electroencephalogram was normal. The diagnosis of SMS was confirmed by a heterozygous mutation in exon 3 of the RAI1 gene on chromosome chr-1717696650 at locus c.388C>T (P.Q130X). In addition, this patient had severe eczema on the skin. The RAI1 mutation c.388C>T (P.Q130X) is a newly reported variant that will help in the clinical identification of SMS and the precise localization of more phenotypically related genes.

Intellectual and Behavioral Phenotypes of Smith-Magenis Syndrome: Comparisons between Individuals with a 17p11.2 Deletion and Pathogenic RAI1 Variant.

AIM: Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder caused by a 17p11.2 deletion or pathogenic variant in the RAI1 gene. SMS is associated with developmental delay, intellectual disability (ID), and major sleep and behavioral disturbances. To explore how genetic variants may affect intellectual functioning and behavior, we compared intellectual and behavioral phenotypes between individuals with a 17p11.2 deletion and pathogenic RAI1 variant. METHOD: We reviewed available clinical records from individuals (aged 0-45 years) with SMS, ascertained through a Dutch multidisciplinary SMS specialty clinic. RESULTS: We included a total of 66 individuals (n = 47, 71.2% with a 17p11.2 deletion and n = 19, 28.8% with a pathogenic RAI1 variant) for whom data were available on intellectual functioning, severity of ID (n = 53), and behavioral problems assessed with the Child Behavior Checklist (CBCL, n = 39). Median full-scale IQ scores were lower (56.0 vs. 73.5, p = 0.001) and the proportion of individuals with more severe ID was higher (p = 0.01) in the 17p11.2 deletion group. Median total CBCL 6-18 scores (73.5 vs. 66.0, p = 0.02) and scores on the sub-scales somatic complaints (68.0 vs. 57.0, p = 0.001), withdrawn/depressed behavior (69.5 vs. 55.0, p = 0.02), and internalizing behavior (66.0 vs. 55.0, p = 0.002) were higher in the RAI1 group. CONCLUSION: The results of this study suggest that 17p11.2 deletions are associated with a lower level of intellectual functioning and less internalizing of problems compared to pathogenic RAI1 variants. The findings of this study may contribute to personalized-management strategies in individuals with SMS.

Direct assessment of overnight parent-child proximity in children with behavioral insomnia: Extending models of operant and classical conditioning.

INTRODUCTION: Explanatory models of behavioral insomnia typically draw on operant learning theory with behavioral techniques focused on altering parent-child interactions to improve sleep. However, there are no data describing parent-child interactions overnight beyond parent report. In this study we used radio frequency identification technology to quantify parent-child proximity overnight in two groups at elevated risk of behavioral insomnia, Angelman syndrome (AS) and Smith-Magenis syndrome (SMS). MATERIALS AND METHODS: Nineteen children aged 4-15 years (8 with AS, 11 with SMS) participated in a week-long at-home assessment of sleep and overnight parent-child proximity. Sleep parameters were recorded using the Philips Actiwatch 2 and proximity data were recorded using custom-built radio frequency identification watches. RESULTS: Three patterns of proximity data between parent-child dyads overnight were evident: "checking" (six with AS, five with SMS), "co-sleeping" (four with SMS) and those who had "no proximity" overnight (two with AS, two with SMS). In the AS group, 25.45% of actigraphy-defined wakes resulted in a parent-child interaction. In the SMS group, 39.34% of wakes resulted in a parent-child interaction. Children who interacted with their parents when settling to sleep were not significantly more likely to interact at waking. DISCUSSION: The novel application of radio frequency identification technology is a feasible method for studying overnight parent-child proximity. Profiles of proximity between participants that are not closely aligned with operant models of behavioral insomnia were evident. These results have significant implications for the etiology of poor sleep and the application of behavioral sleep interventions.

rAAV-CRISPRa therapy corrects Rai1 haploinsufficiency and rescues selective disease features in Smith-Magenis syndrome mice.

Haploinsufficiency in retinoic acid induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), a severe neurodevelopmental disorder characterized by neurocognitive deficits and obesity. Currently, curative treatments for SMS do not exist. Here, we take a recombinant adeno-associated virus (rAAV)-clustered regularly interspaced short palindromic repeats activation (CRISPRa) approach to increase expression of the remaining intact Rai1 allele. Building upon our previous work that found the paraventricular nucleus of hypothalamus plays a central role in SMS pathogenesis, we performed paraventricular nucleus of hypothalamus-specific rAAV-CRISPRa therapy by increasing endogenous Rai1 expression in SMS (Rai1±) mice. We found that rAAV-CRISPRa therapy rescues excessive repetitive behavior, delays the onset of obesity, and partially reduces hyperphagia in SMS mice. Our work provides evidence that rAAV-CRISPRa therapy during early adolescence can boost the expression of healthy Rai1 allele and modify disease progression in a mouse model of Smith-Magenis syndrome.

A diagnosis of Birt-Hogg-Dubé syndrome in individuals with Smith-Magenis syndrome: Recommendation for cancer screening.

We report a series of four unrelated adults with Smith-Magenis syndrome (SMS) and concomitant features of Birt-Hogg-Dubé (BHD) syndrome based upon haploinsufficiency for FLCN and characteristic renal cell carcinomas and/or evidence of cutaneous fibrofolliculomas. Three of the cases constitute the first known association of histopathologically verified characteristic BHD-associated renal tumors in adults with SMS; the fourth was identified to have histologically confirmed skin fibrofolliculomas. Molecular analysis documented second-hit FLCN mutations in two of the three cases with confirmed BHD renal pathology. These cases suggest the need to expand management recommendations for SMS to include kidney cancer surveillance starting at 20 years of age, as per the screening recommendations for BHD syndrome.

A de novo mutation (p.S1419F) of Retinoic acid induced 1 is responsible for a patient with Smith-Magenis syndrome exhibiting schizophrenia.

Smith-Magenis syndrome (SMS, OMIM# 182290) is a rare congenital disorder which characterized by multiple abnormalities involving in craniofacial, skeletal, otorhinolaryngolocial, neurological, behavioral and others. 17p11.2 microdeletion and RAI1 mutations have been proven to be genetic lesions of this disease. However, the relationship between RAI1 variants and different phenotypes is still unclear. The discoveries of more RAI1 mutations in patients with different phenotypes will help to elucidate the pathogenesis of the RAI1 gene. Here, we describe a young patient with schizophrenia and headache as the main clinical presentation, with SMS-like features including depression, sleep disturbance and pain-free status. Whole exome sequencing and Sanger sequencing suggested that a de novo mutation (NM_030665.3: c.4256C > T/p.S1419F) of RAI1 may be the genetic lesion of the patient. The bioinformatic program predicted that the new mutation (p.S1419F), located in an evolutionarily conserved site of RAI1, was deleterious. Further, western blot analysis suggested that the novel mutation may decrease the protein levels of RAI1 in the patient. Hence, we reported a novel mutation of RAI1 in a patient with SMS, schizophrenia and headache. Our study may expand the spectrum of RAI1 mutations which may further contribute to the mechanisms underlying SMS, schizophrenia and headache.

Retinoic acid-induced 1 gene haploinsufficiency alters lipid metabolism and causes autophagy defects in Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disturbance, and no therapy has been developed to alleviate its symptoms or delay disease onset. SMS occurs due to haploinsufficiency of the retinoic acid-induced-1 (RAI1) gene caused by either chromosomal deletion (SMS-del) or RAI1 missense/nonsense mutation. The molecular mechanisms underlying SMS are unknown. Here, we generated and characterized primary cells derived from four SMS patients (two with SMS-del and two carrying RAI1 point mutations) and four control subjects to investigate the pathogenetic processes underlying SMS. By combining transcriptomic and lipidomic analyses, we found altered expression of lipid and lysosomal genes, deregulation of lipid metabolism, accumulation of lipid droplets, and blocked autophagic flux. We also found that SMS cells exhibited increased cell death associated with the mitochondrial pathology and the production of reactive oxygen species. Treatment with N-acetylcysteine reduced cell death and lipid accumulation, which suggests a causative link between metabolic dyshomeostasis and cell viability. Our results highlight the pathological processes in human SMS cells involving lipid metabolism, autophagy defects and mitochondrial dysfunction and suggest new potential therapeutic targets for patient treatment.

Loss of Rai1 enhances hippocampal excitability and epileptogenesis in mouse models of Smith-Magenis syndrome.

Hyperexcitability of brain circuits is a common feature of autism spectrum disorders (ASDs). Genetic deletion of a chromatin-binding protein, retinoic acid induced 1 (RAI1), causes Smith-Magenis syndrome (SMS). SMS is a syndromic ASD associated with intellectual disability, autistic features, maladaptive behaviors, overt seizures, and abnormal electroencephalogram (EEG) patterns. The molecular and neural mechanisms underlying abnormal brain activity in SMS remain unclear. Here we show that panneural Rai1 deletions in mice result in increased seizure susceptibility and prolonged hippocampal seizure duration in vivo and increased dentate gyrus population spikes ex vivo. Brain-wide mapping of neuronal activity pinpointed selective cell types within the limbic system, including the hippocampal dentate gyrus granule cells (dGCs) that are hyperactivated by chemoconvulsant administration or sensory experience in Rai1-deficient brains. Deletion of Rai1 from glutamatergic neurons, but not from gamma-aminobutyric acidergic (GABAergic) neurons, was responsible for increased seizure susceptibility. Deleting Rai1 from the Emx1Cre-lineage glutamatergic neurons resulted in abnormal dGC properties, including increased excitatory synaptic transmission and increased intrinsic excitability. Our work uncovers the mechanism of neuronal hyperexcitability in SMS by identifying Rai1 as a negative regulator of dGC intrinsic and synaptic excitability.

[Genetic diagnosis of a case of Smith-Magenis syndrome due to a rare small-scale deletion].

OBJECTIVE: To report on a case of Smith-Magenis syndrome (SMS) due to a rare small-scale deletion. METHODS: Muscle samples from the the third fetus was collected after the in Medical history and clinical data of the patient were collected. The child and his parents were subjected to chromosome karyotyping analysis, multiplex ligation-dependent probe amplification (MLPA) and copy number variation sequencing (CNV-seq). RESULTS: The child was found to have a normal karyotype. MLPA and CNV-seq detection showed that he has harbored a 1.22 Mb deletion and a 0.3 Mb duplication in the 17p11.2 region. Neither of his parents was found to have similar deletion or duplication. CONCLUSION: The child was diagnosed with SMS due to a rare 1.22 Mb deletion in the 17p11.2 region, which is among the smallest deletions associated with this syndrome.

A unique Smith-Magenis patient with a de novo intragenic deletion on the maternally inherited overexpressed RAI1 allele.

RAI1 is a dosage-sensitive gene whose decreased or increased expression by recurrent and non-recurrent 17p11.2 deletions or duplications causes Smith-Magenis (SMS) or Potocki-Lupski syndromes (PTLS), respectively. Here we report on a 21-year-old female patient showing SMS phenotype who was found to carry a 3.4 kb de novo intragenic RAI1 deletion. Interestingly, a significant increase in RAI1 transcript levels was identified in the patient's, brother's and mother's peripheral blood cells. Allele-specific dosage analysis revealed that the patient's maternally inherited overexpressed RAI1 allele harbors the intragenic deletion, confirming the SMS diagnosis due to the presence of a single wild-type RAI1 functional allele. The mother and brother do not present any PTLS neurologic/behavioral clinical features. Extensive sequencing of RAI1 promoter and predicted regulatory regions showed no potential causative variants accounting for gene overexpression. However, the mother and both children share a novel private missense variant in RAI1 exon 3, currently classified as a VUS (uncertain significance), though predicted by two bioinformatic tools to disrupt the binding site of one specific transcription factor. The reported familial case, the second showing RAI1 overexpression in the absence of RAI1 duplication, may help to understand the regulation of RAI1 dosage sensitivity although its phenotypic effect remains to be determined.

Sleep disturbances and behavior in Smith-Magenis syndrome.

BACKGROUND: The Smith-Magenis syndrome (SMS) shows a collection of neurodevelopmental problems including mild to moderate intellectual disability, change-related anxiety, impulsivity, speech delay, Attention-Deficit/Hyperactivity Disorder (ADH) and sleep disturbances. Sleep disorders, when present, have been treated in several populations with consecutive improvements in cognitive and behavioral aspects. AIMS: To better understand the existing relationships between sleep disturbances and behavioral problems in SMS syndrome this study describes the sleep and behavior problems in the SMS and explores the possible relation between both. METHODS AND PROCEDURES: 17 individuals with SMS (50% males; 11.2 ± 4.9 years old) and 12 individuals with typical development (50% male; 11.1 ± 4.4 years old) were investigated using the Sleep Disturbance Scale for Children and the Child Behavior Checklist. RESULTS: A high percentage (60%) of individuals with SMS have an indication of sleep disorders, being the most frequent disorders the sleep-wake transition disorders, and disorders of initiating and maintaining sleep with sleep latency higher than acceptable and total sleep time below acceptable. More than 94% of the SMS group presented clinical or borderline scores on the total behavioral problems scale. The most common behavioral problems were Externalizing Problems, Thought and Attention, ADH and Aggressive problems. There was a positive correlation between disorders of initiating and maintaining sleep, sleep-wake transition disorders, disorders of arousal, disorders of excessive somnolence and behavioral problems. CONCLUSIONS AND IMPLICATIONS: The worse the sleep disturbances investigated, the more severe the behavioral problems characteristics reinforcing the importance to address the sleep problems in the treatment of SMS individuals.

Relationships between food-related behaviors, obesity, and medication use in individuals with Smith-Magenis syndrome.

BACKGROUND: Smith-Magenis syndrome (SMS) is a complex neurodevelopmental disorder that includes obesity and food-seeking/satiety-related behaviors. AIMS: This study examined associations between food-related/hyperphagic behaviors, weight, and medication use in individuals with SMS. METHODS/PROCEDURES: Caregivers of individuals with SMS in the Parents and Researchers Interested in SMS (PRISMS) Patient Registry completed a demographic/medication questionnaire, the Hyperphagia Questionnaire for Clinical Trials, and the Food Related Problems Questionnaire. OUTCOMES/RESULTS: Among 49 participants (Mage = 16.41 ± 12.73 years, range = 4-69 years, 55% girls/women), individuals with SMS with overweight/obesity (n = 22) had worse overall food-related problems including greater impaired satiety (p < 0.05), maladaptive eating behaviors (p < 0.05), inappropriate response (p < 0.01), and hyperphagia (p < 0.01) compared to individuals of normal/underweight (n = 27). Those taking anti-depressants/anxiolytics (n = 16) had greater maladaptive eating behaviors (p < 0.05), hyperphagic behaviors (p < 0.05), and hyperphagic severity (p < 0.05) than those not taking anti-depressants/anxiolytics (n = 33). Boys/men with SMS had greater maladaptive eating behaviors (p < 0.05), inappropriate response (p < 0.05), and hyperphagic drive (p < 0.01) than girls/women with SMS. CONCLUSIONS/IMPLICATIONS: Maladaptive food-related behaviors were higher in individuals with SMS with overweight/obesity, taking anti-depressants/anxiolytics, or who were male. Medications in this population should be chosen with weight-related side effects in mind.

[Clinical characteristics and genetic analysis of a neonate with Smith-Magenis syndrome].

OBJECTIVE: To explore the clinical features and genetic etiology for a neonate with Smith-Magenis syndrome (SMS). METHODS: Copy number variation sequencing (CNV-seq) was applied to the neonate and his parents, and the genotype-phenotype correlation was analyzed. RESULTS: On the second day after birth, the neonate had presented with pathological jaundice and immunodeficiency. Cranial MRI revealed ventricular enlargement and enlargement of cisterna magna. At 3 months, the infant has presented with square face, prominent forehead, deep-set eyes, hypertelorism, palpebral fissure upward and button noses. Genetic testing showed that he had carried a 2.9 Mb deletion in 17p11.2 region, seq[GRCh37] del(17)(p11.2)(chr17:16 836 379-19 880 992). The same deletion was not found in either parent. CONCLUSION: SMS is mostly diagnosed in child and adulthood, but rarely in neonates. For neonates with SMS, the neurological and behavioral abnormalities have not been shown, but pathological jaundice, CNS abnormalities and immune deficiency may be the characteristics, which require attention of neonatal physicians.

Smith Magenis syndrome: First case of congenital heart defect in a patient with Rai1 mutation.

Smith Magenis syndrome (SMS) is a rare neurobehavioral disorder caused by 17p11.2 microdeletion encompassing Retinoic Acid-Induced 1 (RAI1) gene (90% of cases) or by RAI1 point mutation (10% of cases). The neuropsychological phenotype of individuals with 17p11.2 deletion and in those with RAI1 variants mostly overlaps. However, cardiac defects have been described only in patients with a deletion so far. Here, we present the first case of a patient affected by SMS caused by RAI1 variant in whom a severe congenital pulmonary valve stenosis was diagnosed at birth, requiring trans catheter dilatation in the first month of life. This case expands the phenotypic spectrum associated with RAI1 variants in SMS, describing a previously unreported association with a congenital heart disease.