Ras-responsive element binding protein 1 (RREB1) is a zinc finger transcription factor that is crucial in regulating cell growth, gene expression, and DNA repair. It functions as both a repressor and an activator, with its activity controlled by the MAPK signaling pathway. RREB1 has been implicated in various conditions such as type 2 diabetes (T2D), obesity, and cancer, suggesting its potential as both a biomarker and a therapeutic target for these diseases. While several cases of 6p terminal deletions in the RREB1 gene and one case of Noonan-like RASopathy due to a loss-of-function variant have been reported, this study presents the first case of a pathogenic loss-of-function variant in RREB1 associated with morbid obesity and metabolic disturbances. Our patient, a 16-year-old male, exhibited morbid obesity, metabolic disorders, moderate intellectual disability, and atypical autism symptoms. He was referred to our clinic by the pediatric endocrinology department for genetic evaluation. Initial genetic testing included karyotype analysis and SNP array testing with 700 000 probes. Whole exome sequencing (WES) was then performed on the patient and his family, revealing a de novo novel variant, c.3178_3179del, p.(Glu1060Argfs*37) in the RREB1 gene, which was confirmed by Sanger sequencing. This novel variant underscores the critical role of RREB1 in regulating metabolic processes, particularly obesity. Additionally, the patient's neurodevelopmental delay aligns with previously reported findings of RREB1 loss-of-function variants. These results highlight the need for further research to fully understand the metabolic implications of RREB1 gene loss, with this study providing valuable insights for future investigations.

Deficits in emotion knowledge can impact children's social-emotional interactions, which are particularly evident in children with autism spectrum disorders (ASD). However, consistent evidence regarding emotion knowledge and its individual components across ASD subtypes, as defined by ICD-10, remained limited. This study investigates emotion knowledge development - both as a whole and in seven specific components - in children with ASD, categorized by subtype, and compares them with a matched group of children without ASD using nearest neighbor matching based on gender, age, and language background. The sample includes 79 children with ASD (68 boys, 11 girls; ages 5-10): Childhood Autism (n = 33), Atypical Autism (n = 15), and Asperger's Syndrome (n = 31). Participants completed the Adaptive Test of Emotion Knowledge for Three- to Nine-year-olds (ATEM 3-9). A control group of 152 children without ASD was drawn from the ATEM 3-9 norming sample. Results reveal significant differences in emotion knowledge development across ASD subtypes. Children with Childhood Autism scored significantly lower than children without ASD, whereas children with Asperger's Syndrome or Atypical Autism showed no significant differences compared to the control group. These findings suggest that emotion knowledge deficits in ASD are subtype specific. Future research should account for these distinctions when examining emotional development in children with ASD. Zusammenfassung Komponenten des Emotionswissens bei Subtypen von Kindern mit Autismus-Spektrum- Störungen (ASS) Ein umfassendes Emotionswissen gilt als zentrale Voraussetzung fur gelingende sozial-emotionale Interaktionen. Insbesondere bei Kindern mit Autismus-Spektrum-Storungen (ASS) konnen Defizite in diesem Bereich zu erheblichen Beeintrachtigungen fuhren. Trotz zahlreicher Studien fehlt bislang eine konsistente Evidenz daruber, in welchem Ausmas Kinder mit ASS Einschrankungen im Emotionswissen und dessen Komponenten aufweisen und ob sich diese in Abhangigkeit von den ICD-10-Subtypen systematisch unterscheiden. Die vorliegen-de Studie analysiert die Entwicklung des Emotionswissens - sowohl als ubergeordnetes Konstrukt als auch hinsichtlich sieben spezifischen Teilkomponenten - bei Kindern mit ASS differenziert nach den Subtypen Fruhkindlicher Autismus (n = 33), Atypischer Autismus (n = 15) und Asperger-Syndrom (n = 31). Die Gesamtstichprobe umfasst 79 Kinder mit ASS im Alter von funf bis zehn Jahren (68 Jungen, 11 Madchen). Die Kontrollgruppe bestand aus 152 Kindern ohne ASS aus der Normierungsstichprobe. Die Gruppen wurden mithilfe des Nearest- Neighbor-Matchings basierend auf Geschlecht, Alter und Sprachhintergrund miteinander vergleichbar gemacht. Zur Datenerhebung wurde der Adaptive Test des Emotionswissens fur Drei- bis Neunjahrige (ATEM 3-9) eingesetzt. Die Ergebnisse zeigen signifikante Unterschiede im Emotionswissen sowohl zwischen den ASS-Subtypen als auch im Vergleich zur Kontrollgruppe. Wahrend Kinder mit Fruhkindlichem Autismus signifikant geringere Werte erzielten, unterschieden sich Kinder mit Atypischem Autismus und Asperger-Syndrom nicht signifikant von Kindern ohne ASS. Diese Ergebnisse unterstreichen die Notwendigkeit einer differenzierten Betrachtung von ASS-Subtypen bei der Erforschung und Forderung emotionaler Kompetenzen.

Autism spectrum disorder (ASD) is a heritable neurodevelopmental condition with a complex genetic architecture. Dissecting the interplay between inherited variants and high-impact de novo variants is critical for understanding its etiology. We conducted a family-based study involving 42 families with ASD (139 individuals). Using a targeted next-generation sequencing (NGS) panel of 236 genes, we identified and characterized rare inherited and de novo variants in affected probands, parents, and unaffected siblings. Our analysis revealed a complex genetic landscape marked by diverse inheritance patterns. De novo variants were predominantly observed in individuals with atypical autism, while biparental (homozygous) inheritance was more common in Asperger syndrome. Maternally inherited variants showed significant enrichment in intronic regions, pointing to a potential regulatory role. We also detected variants in several high-confidence ASD risk genes, including SHANK3, MYT1L, MCPH1, NIPBL, and TSC2, converging on pathways central to synaptic function and neurogenesis. Across the cohort, five variants of uncertain significance (VUS) were identified, comprising two inherited variants in ABCC8 and additional variants in CUL23, TSC2, and MCPH1. Our findings underscore the profound genetic heterogeneity of ASD and suggest that distinct genetic mechanisms and inheritance patterns may contribute to different clinical presentations within the spectrum. This highlights the power of family-based genomic analyses in elucidating the complex interplay of inherited and de novo variants that underlies ASD.

Nonsense-mediated mRNA decay (NMD) plays a crucial role in degrading aberrant transcripts with premature termination codons, with the Up-frameshift (UPF) protein family-UPF1, UPF2, and UPF3A/UPF3B-being vital components of this machinery. While several variants in genes encoding UPF2 and UPF3A/3B have been associated with neurodevelopmental disorders, only three germline UPF1 variants have been reported to date. Here, we report a male patient with a de novo missense variant, p.(Ala526Thr), in a highly conserved helicase motif of UPF1. The patient presented with moderate intellectual disability (ID), atypical autism, attention deficit hyperactivity disorder (ADHD), and behavioral disturbances. The common features observed among the four patients with UPF1 variants are moderate to severe ID and developmental delays in motor and verbal skills. A comparison across the disorders related to the UPF genes suggests that neurodevelopmental delay, including ID and impaired verbal skills, is a common feature, and these disorders may collectively be referred to as UPF-related neurodevelopmental disorders (NDDs). ADHD, autism, seizures, hypotonia, and non-specific dysmorphic features are also reported in some patients, suggesting that these disorders can be classified as non-specific intellectual disability syndromes. However, further studies are necessary to elucidate genotype-phenotype correlations and the molecular mechanisms underlying these rare disorders, particularly those related to UPF1.

This single-case study was conducted on a 34-year-old woman diagnosed with therapy-resistant depression and co-occurring atypical autism. The subject had been kept on the same medications for eight years despite her condition not improving and at the same time experiencing side effects. Previous studies and patient experiences suggest that many physicians are reluctant to end prescribed medication even if the patient is experiencing inadequate benefits and questionable effects. Co-occurring diseases often share overlapping symptoms, which can make accurate diagnosis and treatment more challenging, such as for patients with depression and autism. The problem becomes even more complicated when looking into the long-term treatment of depression occurring alongside autism spectrum disorder (ASD). The focus of conducting this case study was to determine the effect of DAT on a patient with confirmed therapy-resistant depression and ASD and if DAT would provide long-term benefit for the subject. The study's results indicate that the patient experienced both quick improvement and long-term positive outcomes of DAT and is now in her 10th-year symptom-free.