Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in KMT2D/MLL2 and KDM6A/UTX, two interacting chromatin modifier responsible respectively for 56–75% and 5–8% of the cases. To date, three KS patients with mosaic KMT2D deletions in blood lymphocytes have been described. We report on three additional subjects displaying KMT2D gene mosaics including one in which a single nucleotide change results in a new frameshift mutation (p.L1199HfsX7), and two with already-known nonsense mutations (p.R4484X and p.R5021X). Consistent with previously published cases, mosaic KMT2D mutations may result in mild KS facial dysmorphisms and clinical and neurobehavioral features, suggesting that these characteristics could represent the handles for genetic testing of individuals with slight KS-like traits.

Atypical development of numerical cognition (dyscalculia) may increase the onset of neuropsychiatric symptoms, especially when untreated, and it may have long-term detrimental social consequences. However, evidence-based treatments are still lacking. Despite plenty of studies investigating the effects of transcranial electrical stimulation (tES) on numerical cognition, a systematized synthesis of results is still lacking. In the present systematic review (PROSPERO ID: CRD42021271139), we found that the majority of reports (20 out of 26) showed the effectiveness of tES in improving both number (80%) and arithmetic (76%) processing. In particular, anodal tDCS (regardless of lateralization) over parietal regions, bilateral tDCS (regardless of polarity/lateralization) over frontal regions, and tRNS (regardless of brain regions) strongly enhance number processing. While bilateral tDCS and tRNS over parietal and frontal regions and left anodal tDCS over frontal regions consistently improve arithmetic skills. In addition, tACS seems to be more effective than tDCS at ameliorating arithmetic learning. Despite the variability of methods and paucity of clinical studies, tES seems to be a promising brain-based treatment to enhance numerical cognition. Recommendations for clinical translation, future directions, and limitations are outlined.

7q11.23 Microduplication (dup7q11.23) syndrome is a rare autosomal dominant disorder due to a recurring 1.5 to 1.8 Mb duplication of the Williams–Beuren Syndrome critical region. Dup7q11.23 has been associated with several neuro-behavioral characteristics such as low cognitive and adaptive functioning, expressive language impairment, anxiety problems and autistic features. In the present study, we analyze the clinical features of ten individuals in which array-CGH detected dup7q11.23, spanning from 1.4 to 2.1 Mb. The clinical characteristics associated with dup7q11.23 are discussed with respect to its reciprocal deletion. Consistent with previous studies, we confirm that individuals with dup7q11.23 syndrome do not have a homogeneous clinical profile, although some recurring dysmorphic features were found, including macrocephaly, prominent forehead, elongated palpebral fissures, thin lip vermilion and microstomia. Minor congenital malformations include patent ductus arteriosus, cryptorchidism and pes planus. A common finding is hypotonia and joint laxity, resulting in mild motor delay. Neuropsychological and psychodiagnostic assessment confirm that mild cognitive impairment, expressive language deficits and anxiety are recurring neurobehavioral features. New insights into adaptive, psychopathological and neurodevelopmental profiles are discussed.

Malan Syndrome (MS) is an ultra-rare overgrowth genetic syndrome due to heterozygous variants or deletions in the Nuclear Factor I X (NFIX) gene. It is characterized by an unusual facial phenotype, generalized overgrowth, intellectual disability (ID) and behavioral problems. Even though limitations in cognitive and adaptive functioning have been previously described, systematic studies on MS cohorts are still lacking. Here, we aim to define the cognitive and adaptive behavior profile of MS children and adolescents, providing quantitative data from standardized evaluations. Subjects included in this study were evaluated from October 2020 to January 2022 and the study is based on a retrospective data archive: fifteen MS individuals were recruited and underwent evaluation with Wechsler Intelligence Scales, Leiter International Performance Scales and Griffith Mental Development Scales for cognitive profiles and with Vineland Adaptive Behavior Scales-II Edition (VABS-II) for adaptive functioning. Language skills and visuomotor integration abilities were assessed too. Comparisons and correlations between scales and subtests were performed. All the assessed MS individuals showed both low cognitive and adaptive functioning. One subject presented with mild ID, five had moderate ID and eight showed severe ID. One female toddler received a diagnosis of psychomotor delay. Linguistic skills were impaired in all individuals, with language comprehension relatively more preserved. Results revealed significant differences between VABS-II subdomains and a strong relationship between cognitive and adaptive functioning. All subjects exhibited mild to moderate ID and adaptive behavior lower than normal, with communication skills being the most affected. Regarding the daily living skills domain, personal and community subscale scores were dramatically lower than for the domestic subdomain, highlighting the importance of considering behavior within developmental and environmental contexts. Our cognitive and adaptive MS characterization provides a more accurate quantitative MS profiling, which is expected to help clinicians to better understand the complexity of this rare disorder.

Noonan syndrome (NS) is a dominant clinically variable and genetically heterogeneous developmental disorder caused by germ-line mutations encoding components of the Ras–MAPK signaling pathway. A few studies have investigated psychopathological features occurring in individuals with NS, although they were poorly analyzed. The aim of the present work is to investigate the psychopathological features in children and adolescents with NS focusing on depressive and hypo-manic symptoms. Thirty-seven subjects with molecularly confirmed diagnosis were systematically evaluated through a psychopathological assessment. In addition, an evaluation of the cognitive level was performed. Our analyses showed a high recurrence of attention deficit and hyperactivity disorder symptoms, emotional dysregulation, irritability, and anxiety symptomatology. The mean cognitive level was on the average. The present study provides new relevant information on psychopathological features in individuals with NS. The implications for clinicians are discussed including the monitoring of mood disorders in a clinical evolution.

KBG syndrome is a rare multisystem developmental disorder caused by ankyrin repeat domain-containing protein 11 (ANKRD11) gene haploinsufficiency, resulting from either intragenic loss-of-function mutations or microdeletions encompassing the gene. Concerning the behavioral phenotype, a limited amount of research has been focused on attention deficit and hyperactivity disorder, autistic-like features, anxiety and impairments in emotion regulation, and no study has provided a systematic assessment. The aim of the present work is to investigate the psychopathological profile in children, adolescents, and young adults with KBG syndrome. Seventeen subjects with molecularly confirmed diagnoses were evaluated to investigate cognitive abilities and psychopathological features. Parametric and nonparametric indexes were used to describe the patient cohort according to type and distribution of specific measures. The KBG subjects were characterized by a low mean IQ score, with a distribution characterized by a variability similar to that occurring in the general population. Prevalence of neuropsychiatric disorders were computed as well as the corresponding confidence intervals to compare their prevalence to that reported for the general population. The KBG subjects were characterized by higher prevalence of obsessive-compulsive, tic, depressive and attention deficit and hyperactivity disorders. Obsessive-compulsive disorder is a peculiar aspect characterizing the psychopathological profile of KBG patients, which does not seem to be related to the cognitive level. The present study provides new relevant information towards the definition of a psychopathological phenotype of KBG syndromes useful to plan a better treatment for patients.