Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders.

The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl- channels and Cl-/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3-/- mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.

Pathogenic variants in SOX11 mimicking Pitt-Hopkins syndrome phenotype.

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder characterised by severe intellectual disability (ID), distinctive facial features and autonomic nervous system dysfunction, caused by TCF4 haploinsufficiency. We clinically diagnosed with PTHS a 14 6/12 -year-old female, who had a normal status of TCF4. The pathogenic c.667del (p.Asp223MetfsTer45) variant in SOX11 was identified through whole exome sequencing (WES). SOX11 variants were initially reported to cause Coffin-Siris syndrome (CSS), characterised by growth restriction, moderate ID, coarse face, hypertrichosis and hypoplastic nails. However, recent studies have provided evidence that they give rise to a distinct neurodevelopmental disorder. To date, SOX11 variants are associated with a variable phenotype, which has been described to resemble CSS in some cases, but never PTHS. By reviewing both clinically and genetically 32 out of 82 subjects reported in the literature with SOX11 variants, for whom detailed information are provided, we found that 7/32 (22%) had a clinical presentation overlapping PTHS. Furthermore, we made a confirmation that overall SOX11 abnormalities feature a distinctive disorder characterised by severe ID, high incidence of microcephaly and low frequency of congenital malformations. Purpose of the present report is to enhance the role of clinical genetics in assessing the individual diagnosis after WES results.

POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum.

POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.

Neuropsychological features in RASopathies: A pilot study on parent training program involving families of children with Noonan syndrome.

Noonan syndrome (NS) is a clinical variable multisystem disorder caused by mutations in genes encoding proteins involved in the RAS/mitogen-activated protein kinase signaling pathway. NS is characterized by a distinctive facies, short stature, and congenital heart defects. Psychomotor delay, learning difficulties, and social deficits are also common. Furthermore, behavioral and attention problems can be reckoned as a key symptom in NS, with functioning resembling the patterns observed in attention deficit hyperactivity disorder (ADHD). The complex behavioral phenotype has great impact on the quality of life and raises demanding management issues also for patients' families. Parent management training (PMT) is recommended as first-line treatment for ADHD; however, no study has been performed to test the efficacy of PMT in NS, thus far. The aim of this pilot study is the implementation and evaluation of a PMT dedicated to NS families. Parents of seven children with NS were recruited and underwent to a 10-session PMT. Three different questionnaires were administered to both parents: Conners Parent Rating Scales, Parenting Stress Index Short Form (PSI-SF), and Alabama Parenting Questionnaire (APQ). Our findings on this first small cohort of families indicate that positive perception and satisfaction about the child and the interaction with him increased in mothers after the intervention, as measured respectively by PSI-SF difficult child (DC) and PSI-SF parent-child dysfunctional interaction (PCDI), while mothers' level of stress decreased after the PMT, as indicated by PSI-SF total scores. Furthermore, APQ positive parenting, which measures behaviors of positive relationship with the child, increased in mothers after the intervention. Statistical analysis on fathers' questionnaires did not show significant differences after the PMT sessions. This pilot study suggests that PMT is a promising intervention for parents of NS children with behavioral and ADHD symptoms. Changes in mothers' attitudes and distress indicate that behaviorally oriented programs may help parents to manage with NS phenotype.

Congenital heart defects in molecularly confirmed KBG syndrome patients.

Congenital heart defects (CHDs) are known to occur in 9%-25% of patients with KBG syndrome. In this study we analyzed the prevalence and anatomic types of CHDs in 46 personal patients with KBG syndrome, carrying pathogenetic variants in ANKRD11 or 16q24.3 deletion, and reviewed CHDs in patients with molecular diagnosis of KBG syndrome from the literature. CHD was diagnosed in 15/40 (38%) patients with ANKRD11 variant, and in one patient with 16q24.3 deletion. Left ventricular outflow tract obstructions have been diagnosed in 9/15 (60%), subaortic or muscular ventricular septal defect in 5/15 (33%), dextrocardia in 1/15 (8%). The single patient with 16q24.3 deletion and CHD had complete atrioventricular septal defect (AVSD) with aortic coarctation. Review of KBG patients from the literature and present series showed that septal defects have been diagnosed in 44% (27/61) of the cases, left ventricular tract obstructions in 31% (19/61), AVSD in 18% (11/61). Septal defects have been diagnosed in 78% of total patients with 16q24.3 deletion. Valvar anomalies are frequently diagnosed, prevalently involving the left side of the heart. A distinctive association with AVSD is identifiable and could represent a marker to suggest the diagnosis in younger patients. In conclusion, after precise molecular diagnosis and systematic cardiological screening the prevalence of CHD in KBG syndrome seems to be higher than previously reported in clinical articles. In addition to septal defects, left-sided anomalies and AVSD should be considered. Clinical management of KBG syndrome should include accurate and detailed echocardiogram at time of diagnosis.

Hereditary spastic paraplegia is a novel phenotype for germline de novo ATP1A1 mutation.

Dominant mutations in ATP1A1, encoding the alpha-1 isoform of the Na+ /K+ -ATPase, have been recently reported to cause an axonal to intermediate type of Charcot-Marie-Tooth disease (ie, CMT2DD) and a syndrome with hypomagnesemia, intractable seizures and severe intellectual disability. Here, we describe the first case of hereditary spastic paraplegia (HSP) caused by a novel de novo (p.L337P) variant in ATP1A1. We provide evidence for the causative role of this variant with functional and homology modeling studies. This finding expands the phenotypic spectrum of the ATP1A1-related disorders, adds a piece to the larger genetic puzzle of HSP, and increases knowledge on the molecular mechanisms underlying inherited axonopathies (ie, CMT and HSP).

TUBB Variants Underlying Different Phenotypes Result in Altered Vesicle Trafficking and Microtubule Dynamics.

Tubulinopathies are rare neurological disorders caused by alterations in tubulin structure and function, giving rise to a wide range of brain abnormalities involving neuronal proliferation, migration, differentiation and axon guidance. TUBB is one of the ten ß-tubulin encoding genes present in the human genome and is broadly expressed in the developing central nervous system and the skin. Mutations in TUBB are responsible for two distinct pathological conditions: the first is characterized by microcephaly and complex structural brain malformations and the second, also known as "circumferential skin creases Kunze type" (CSC-KT), is associated to neurological features, excess skin folding and growth retardation. We used a combination of immunocytochemical and cellular approaches to explore, on patients' derived fibroblasts, the functional consequences of two TUBB variants: the novel mutation (p.N52S), associated with basal ganglia and cerebellar dysgenesis, and the previously reported variant (p.M73T), linked to microcephaly, corpus callosum agenesis and CSC-KT skin phenotype. Our results demonstrate that these variants impair microtubule (MT) function and dynamics. Most importantly, our studies show an altered epidermal growth factor (EGF) and transferrin (Tf) intracellular vesicle trafficking in both patients' fibroblasts, suggesting a specific role of TUBB in MT-dependent vesicular transport.

Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia.

Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5% in our cohort of unrelated patients screened by targeted next-generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders.

Learning by observation and learning by doing in Down and Williams syndromes.

New skills may be learned by active experience (experiential learning or learning by doing) or by observation of others' experience (learning by observation). In general, learning by observation reduces the time and the attempts needed to learn complex actions and behaviors. The present research aimed to compare learning by observation and learning by doing in two clinical populations with different etiology of intellectual disability (ID), as individuals with Down syndrome (DS) and individuals with Williams syndrome (WS), with the hypothesis that specific profiles of learning may be found in each syndrome. To this end, we used a mixture of new and existing data to compare the performances of 24 individuals with DS, 24 individuals with WS and 24 typically developing children on computerized tasks of learning by observation or learning by doing. The main result was that the two groups with ID exhibited distinct patterns of learning by observation. Thus, individuals with DS were impaired in reproducing the previously observed visuo-motor sequence, while they were as efficient as TD children in the experiential learning task. On the other hand, individuals with WS benefited from the observational training while they were severely impaired in detecting the visuo-motor sequence in the experiential learning task (when presented first). The present findings reinforce the syndrome-specific hypothesis and the view of ID as a variety of conditions in which some cognitive functions are more disrupted than others because of the differences in genetic profile and brain morphology and functionality. These findings have important implications for clinicians, who should take into account the genetic etiology of ID in developing learning programs for treatment and education.

Clinical and Neurobehavioral Features of Three Novel Kabuki Syndrome Patients with Mosaic KMT2D Mutations and a Review of Literature.

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.

Cognitive, adaptive, and behavioral features in Joubert syndrome.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive cerebellar and brainstem malformation recognizable on brain imaging, the so-called molar tooth sign. The full spectrum of cognitive and behavioral phenotypes typical of JS is still far from being elucidated. The aim of this multicentric study was to define the clinical phenotype and neurobehavioral features of a large cohort of subjects with a neuroradiologically confirmed diagnosis of JS. Fifty-four patients aged 10 months to 29 years were enrolled. Each patient underwent a neurological evaluation as well as psychiatric and neuropsychological assessments. Global cognitive functioning was remarkably variable with Full IQ/General Quotient ranging from 32 to 129. Communication skills appeared relatively preserved with respect to both Daily Living and Socialization abilities. The motor domain was the area of greatest vulnerability, with a negative impact on personal care, social, and academic skills. Most children did not show maladaptive behaviors consistent with a psychiatric diagnosis but approximately 40% of them presented emotional and behavioral problems. We conclude that intellectual disability remains a hallmark but cannot be considered a mandatory diagnostic criterion of JS. Despite the high variability in the phenotypic spectrum and the extent of multiorgan involvement, nearly one quarter of JS patients had a favorable long-term outcome with borderline cognitive deficit or even normal cognition. Most of JS population also showed relatively preserved communication skills and overall discrete behavioral functioning in everyday life, independently from the presence and/or level of intellectual disability. © 2016 Wiley Periodicals, Inc.

A Novel Mutation in RPL10 (Ribosomal Protein L10) Causes X-Linked Intellectual Disability, Cerebellar Hypoplasia, and Spondylo-Epiphyseal Dysplasia.

RPL10 encodes ribosomal protein L10 (uL16), a highly conserved multifunctional component of the large ribosomal subunit, involved in ribosome biogenesis and function. Using X-exome resequencing, we identified a novel missense mutation (c.191C>T; p.(A64V)) in the N-terminal domain of the protein, in a family with two affected cousins presenting with X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia (SED). We assessed the impact of the mutation on the translational capacity of the cell using yeast as model system. The mutation generates a functional ribosomal protein, able to complement the translational defects of a conditional lethal mutation of yeast rpl10. However, unlike previously reported mutations, this novel RPL10 missense mutation results in an increase in the actively translating ribosome population. Our results expand the mutational and clinical spectrum of RPL10 identifying a new genetic cause of SED and highlight the emerging role of ribosomal proteins in the pathogenesis of neurodevelopmental disorders.

Behavioral phenotype in Costello syndrome with atypical mutation: a case report.

Costello syndrome (CS) is a rare genetic disorder caused, in the majority of cases, by germline missense HRAS mutations affecting Gly(12) promoting enhanced signaling through the MAPK and PI3K-AKT signaling cascades. In general, the cognitive profile in CS is characterized by intellectual disability ranging from mild to severe impairment. The first published descriptions of behavior in CS children underlined the presence of irritability and shyness at younger ages with sociable personality and good empathic skills after 4-5 years of age, however some recent studies have reported autistic traits. We report on a 7-year-old boy heterozygous for a rare duplication of codon 37 (p.E37dup) in HRAS, manifesting impaired social interaction and non-verbal communication and with circumscribed interests. These additional features improve phenotype delineation in individuals with rare HRAS mutations, facilitating the development of specific behavioral treatments which could lead to improvement in cases of autism spectrum disorder.

Behavioral profile in RASopathies.

Here, we describe neurobehavioral features in patients with RASopathies (i.e., Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome), developmental disorders caused by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade. Parents of 70 individuals with a RASopathy were asked to fill out the following questionnaires: Child Behavior Checklist (CBCL), Social Communication Questionnaire version lifetime (SCQ-L), and Modified Checklist for Autism in toddlers (M-CHAT). Data analysis indicated high rates of internalizing (37%) and externalizing problems (31%) on CBCL. Scores over the cut-off were documented in 64% of patients with cardiofaciocutaneous syndrome, 44% with Costello syndrome, and 12% with Noonan syndrome on SCQ-L/M-CHAT. Our findings indicate that mutations promoting dysregulation of the RAS-MAPK cascade mark an increased psychopathological risk and highlight that autistic-like behavior could be underdiagnosed in patients with RASopathies.

Corrigendum: PTCHD1 gene mutation/deletion: the cognitive-behavioral phenotyping of four case reports.

[This corrects the article DOI: 10.3389/fpsyt.2023.1327802.].

Evolution of neuropsychological and behavioral profile in a cohort of pediatric patients with Becker muscular dystrophy in a longitudinal study.

It has long been reported that neuropsychological deficits may be present in dystrophinopathies, specifically non-progressive cognitive impairment and a global deficit in executive functions; this neurocognitive profile has been less explored in patients with Becker than Duchenne muscular dystrophy (BMD/DMD). We conducted a longitudinal study to explore the evolution of neuropsychological and behavioural profile in a cohort of paediatric BMD. Seventeen patients with BMD without intellectual disability were assessed using a full battery of tests, including intellectual, adaptive and executive functioning, language and behavioral features. Tests were performed at baseline and after 12 months. The results showed adequate cognitive and adaptive profile with falls in Working Memory, as well as lower scores in executive functions. An improvement was observed in Processing Speed. Behavioral questionnaires confirmed a negative trend, while in normal ranges. We found a statistically significant difference between T0 and T1 in some items exploring executive functions. No statistically significant difference was observed stratifying patients by mutation site or IQ level. In conclusion, our study suggests that BMD patients have a stable neurocognitive profile, while a deflection in the executive functions may be observed. We recommend a careful monitoring to intercept learning disabilities and promptly start a multimodal rehabilitation.

Neurobehavioral phenotype observed in KBG syndrome caused by ANKRD11 mutations.

KBG syndrome is a rare disease characterized by typical facial dysmorphism, macrodontia of upper central incisors, skeletal abnormalities, and developmental delay. Recently, mutations in ANKRD11 gene have been identified in a subset of patients with KBG syndrome, while a contiguous gene deletion syndrome involving 16q24.3 region (including ANKRD11) was delineated in patients with facial dysmorphism, autism, intellectual disability, and brain abnormalities. Although numerous evidences point to a central causative role of ANKRD11 in the neurologic features of these patients, their neurocognitive and behavior phenotypes are still poorly characterized. Herein, we report the complete neurological and psychiatric features observed in two patients with KBG syndrome due to ANKRD11 mutations. Both patients show intellectual disabilities, severe impairment in communication skills, deficits in several aspects of executive functions and working memory and anxious traits. Their features are compared with those of previously reported patients with KBG syndrome aiding in the delineation of neurocognitive phenotype associated to ANKRD11 mutations.

"Corp-Osa-Mente", a Combined Psychosocial-Neuropsychological Intervention for Adolescents and Young Adults with Fragile X Syndrome: An Explorative Study.

Fragile X Syndrome is the most known inherited form of intellectual disability due to an expansion in the full mutation range (>200 CGG repeats) of the promoter region of the FMR1 gene located on X chromosomes leading to gene silencing. Despite clear knowledge of the cognitive-behavioral phenotype of FXS and the necessity of tailored interventions, empirical research on the effectiveness of behavioral treatments among patients with FXS is still lacking, with studies on adolescents and young adults even more insufficient. Here we present "Corposamente", a combined psychosocial-neuropsychological intervention conducted with a group of ten adolescents/young adults with FXS, who are non-ASD and without significant behavioral problems. In total, 20 sessions were performed, alternating between online and face-to-face meetings. At the end of the intervention, participants, family members and participants' educators anonymously completed a survey that was designed around key areas of improvement as well as treatment satisfaction. The survey results indicated that participants improved mostly in their ability to cope with negative emotions and that occupational intervention was considered the most effective technique both from families and participants. Our exploratory study suggests that group therapy for the management of the FXS cognitive-behavioral phenotype may be a promising approach to continue to pursue, mostly in adolescence when the environmental demands increase.

PTCHD1 gene mutation/deletion: the cognitive-behavioral phenotyping of four case reports.

Introduction: X-linked PTCHD1 gene has recently been pointed as one of the most interesting candidates for involvement in neurodevelopmental disorders (NDs), such as intellectual disability (ID) and autism spectrum disorder (ASD). PTCHD1 encodes the patched domain-containing protein 1 (PTCHD1), which is mainly expressed in the developing brain and adult brain tissues. To date, major studies have focused on the biological function of the PTCHD1 gene, while the mechanisms underlying neuronal alterations and the cognitive-behavioral phenotype associated with mutations still remain unclear. Methods: With the aim of incorporating information on the clinical profile of affected individuals and enhancing the characterization of the genotype-phenotype correlation, in this study, we analyze the clinical features of four individuals (two children and two adults) in which array-CGH detected a PTCHD1 deletion or in which panel for screening non-syndromal XLID (X-linked ID) detected a PTCHD1 gene variant. We define the neuropsychological and psychopathological profiles, providing quantitative data from standardized evaluations. The assessment consisted of clinical observations, structured interviews, and parent/self-reported questionnaires. Results: Our descriptive analysis align with previous findings on the involvement of the PTCHD1 gene in NDs. Specifically, our patients exhibited a clinical phenotype characterized by psychomotor developmental delay- ID of varying severity. Interestingly, while ID during early childhood was associated with autistic-like symptomatology, this interrelation was no longer observed in the adult subjects. Furthermore, our cohort did not display peculiar dysmorphic features, congenital abnormalities or comorbidity with epilepsy. Discussion: Our analysis shows that the psychopathological and behavioral comorbidities along with cognitive impairment interfere with development, therefore contributing to the severity of disability associated with PTCHD1 gene mutation. Awareness of this profile by professionals and caregivers can promote prompt diagnosis as well as early cognitive and occupational enhancement interventions.

Attention deficit hyperactivity disorder and cognitive function in Duchenne muscular dystrophy: phenotype-genotype correlation.

OBJECTIVES: To assess attention deficit hyperactivity disorder (ADHD) in boys affected by Duchenne muscular dystrophy (DMD) and to explore the relationship with cognitive abilities and genetic findings. STUDY DESIGN: Boys with DMD (n = 103; 4-17 years of age, mean: 12.6) were assessed using a cognitive test (Wechsler scales). Assessment of ADHD was based on the Diagnostic Statistical Manual, Fourth Edition, Text Revision criteria and on the long version of the Conners Parents and Teachers Rating Scales. RESULTS: ADHD was found in 33 of the 103 boys with DMD. Attention problems together with hyperactivity (17/33) or in isolation (15/33) were more frequent than hyperactivity alone, which was found in 1 patient. Intellectual disability (ID) was found in 27/103 (24.6%). Sixty-two of the 103 boys had no ID and no ADHD, 9 had ID but no ADHD, 14 had ADHD but no ID, and 18 had both. ADHD occurred more frequently in association with mutations predicted to affect Dp140 expression (exon 45-55) and in those with mutations predicted to affect all dystrophin product, including Dp71 (ie, those that have promoter region and specific first exon between exons 62 and 63 but were also relatively frequent). CONCLUSIONS: Our results suggest that ADHD is a frequent feature in DMD. The risk of ADHD appears to be higher in patients carrying mutations predicted to affect dystrophin isoforms expressed in the brain and are known to be associated with higher risk of cognitive impairment.