Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement.

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.

Prenatal vs postnatal diagnosis of 22q11.2 deletion syndrome: cardiac and noncardiac outcomes through 1 year of age.

BACKGROUND: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis. OBJECTIVE: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome. STUDY DESIGN: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site. RESULTS: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019). CONCLUSION: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection.

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD.

Chromosomal Microarray in Patients with Non-Syndromic Autism Spectrum Disorders in the Clinical Routine of a Tertiary Hospital.

Autism spectrum disorders (ASD) comprise a group of neurodevelopmental disorders (NDD) characterized by deficits in communication and social interaction, as well as repetitive and restrictive behaviors, etc. The genetic implications of ASD have been widely documented, and numerous genes have been associated with it. The use of chromosomal microarray analysis (CMA) has proven to be a rapid and effective method for detecting both small and large deletions and duplications associated with ASD. In this article, we present the implementation of CMA as a first-tier test in our clinical laboratory for patients with primary ASD over a prospective period of four years. The cohort was composed of 212 individuals over 3 years of age, who met DSM-5 diagnostic criteria for ASD. The use of a customized array-CGH (comparative genomic hybridization) design (KaryoArray®) found 99 individuals (45.20%) with copy number variants (CNVs); 34 of them carried deletions (34.34%) and 65 duplications (65.65%). A total of 28 of 212 patients had pathogenic or likely pathogenic CNVs, representing approximately 13% of the cohort. In turn, 28 out of 212 (approximately 12%) had variants of uncertain clinical significance (VUS). Our findings involve clinically significant CNVs, known to cause ASD (syndromic and non-syndromic), and other CNVs previously related to other comorbidities such as epilepsy or intellectual disability (ID). Lastly, we observed new rearrangements that will enhance the information available and the collection of genes associated with this disorder. Our data also highlight that CMA could be very useful in diagnosing patients with essential/primary autism, and demonstrate the existence of substantial genetic and clinical heterogeneity in non-syndromic ASD individuals, underscoring the continued challenge for genetic laboratories in terms of its molecular diagnosis.

Prenatal Screening and Diagnostic Considerations for 22q11.2 Microdeletions.

Diagnosis of a chromosome 22q11.2 microdeletion and its associated deletion syndrome (22q11.2DS) is optimally made early. We reviewed the available literature to provide contemporary guidance and recommendations related to the prenatal period. Indications for prenatal diagnostic testing include a parent or child with the 22q11.2 microdeletion or suggestive prenatal screening results. Definitive diagnosis by genetic testing of chorionic villi or amniocytes using a chromosomal microarray will detect clinically relevant microdeletions. Screening options include noninvasive prenatal screening (NIPS) and imaging. The potential benefits and limitations of each screening method should be clearly conveyed. NIPS, a genetic option available from 10 weeks gestational age, has a 70-83% detection rate and a 40-50% PPV for most associated 22q11.2 microdeletions. Prenatal imaging, usually by ultrasound, can detect several physical features associated with 22q11.2DS. Findings vary, related to detection methods, gestational age, and relative specificity. Conotruncal cardiac anomalies are more strongly associated than skeletal, urinary tract, or other congenital anomalies such as thymic hypoplasia or cavum septi pellucidi dilatation. Among others, intrauterine growth restriction and polyhydramnios are additional associated, prenatally detectable signs. Preconception genetic counselling should be offered to males and females with 22q11.2DS, as there is a 50% risk of transmission in each pregnancy. A previous history of a de novo 22q11.2 microdeletion conveys a low risk of recurrence. Prenatal genetic counselling includes an offer of screening or diagnostic testing and discussion of results. The goal is to facilitate optimal perinatal care.

Gathering the Stakeholder's Perspective: Experiences and Opportunities in Rare Genetic Disease Research.

BACKGROUND: Research participant feedback is rarely collected; therefore, investigators have limited understanding regarding stakeholders' (affected individuals/caregivers) motivation to participate. Members of the Genes to Mental Health Network (G2MH) surveyed stakeholders affected by copy number variants (CNVs) regarding perceived incentives for study participation, opinions concerning research priorities, and the necessity for future funding. Respondents were also asked about feelings of preparedness, research burden, and satisfaction with research study participation. METHODS: Modified validated surveys were used to assess stakeholders´ views across three domains: (1) Research Study Enrollment, Retainment, Withdrawal, and Future Participation; (2) Overall Research Experience, Burden, and Preparedness; (3) Research Priorities and Obstacles. Top box score analyses were performed. RESULTS: A total of 704 stakeholders´ responded from 29 countries representing 55 CNVs. The top reasons for initial participation in the research included reasons related to education and altruism. The top reasons for leaving a research study included treatment risks and side effects. The importance of sharing research findings and laboratory results with stakeholders was underscored by participants. Most stakeholders reported positive research experiences. CONCLUSIONS: This study provides important insight into how individuals and families affected with a rare CNV feel toward research participation and their overall experience in rare disease research. There are clear targets for areas of improvement for study teams, although many stakeholders reported positive research experiences. Key findings from this international survey may help advance collaborative research and improve the experience of participants, investigators, and other stakeholders moving forward.

Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients.

BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.

Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.

PURPOSE: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. METHODS: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. RESULTS: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. CONCLUSION: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.

Broadening the phenotypic spectrum of EVEN-PLUS syndrome through identification of HSPA9 pathogenic variants in the original EVE dysplasia family and two sibs with milder facial phenotype.

EVEN-PLUS syndrome is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the mitochondrial chaperone called mortalin, encoded by HSPA9. This genetic disorder, presenting with several overlapping features with CODAS syndrome, is characterized by the involvement of the Epiphyses, Vertebrae, Ears, and Nose (EVEN), PLUS associated findings. Only five individuals presenting with the EVEN-PLUS phenotype and biallelic variants in HSPA9 have been published. Here, we expand the phenotypic and molecular spectrum associated with this disorder, reporting two sibs with a milder phenotype and compound heterozygous pathogenic variants (a recurrent variant and a novel one). Also, we confirm a homozygous pathogenic variant in the family originally reported as EVE dysplasia.

Variability in Phelan-McDermid Syndrome in a Cohort of 210 Individuals.

Phelan-McDermid syndrome (PMS, OMIM# 606232) results from either different rearrangements at the distal region of the long arm of chromosome 22 (22q13.3) or pathogenic sequence variants in the SHANK3 gene. SHANK3 codes for a structural protein that plays a central role in the formation of the postsynaptic terminals and the maintenance of synaptic structures. Clinically, patients with PMS often present with global developmental delay, absent or severely delayed speech, neonatal hypotonia, minor dysmorphic features, and autism spectrum disorders (ASD), among other findings. Here, we describe a cohort of 210 patients with genetically confirmed PMS. We observed multiple variant types, including a significant number of small deletions (<0.5 Mb, 64/189) and SHANK3 sequence variants (21 cases). We also detected multiple types of rearrangements among microdeletion cases, including a significant number with post-zygotic mosaicism (9.0%, 17/189), ring chromosome 22 (10.6%, 20/189), unbalanced translocations (de novo or inherited, 6.4%), and additional rearrangements at 22q13 (6.3%, 12/189) as well as other copy number variations in other chromosomes, unrelated to 22q deletions (14.8%, 28/189). We compared the clinical and genetic characteristics among patients with different sizes of deletions and with SHANK3 variants. Our findings suggest that SHANK3 plays an important role in this syndrome but is probably not uniquely responsible for all the spectrum features in PMS. We emphasize that only an adequate combination of different molecular and cytogenetic approaches allows an accurate genetic diagnosis in PMS patients. Thus, a diagnostic algorithm is proposed.

The natural history of adults with Rubinstein-Taybi syndrome: a families-reported experience.

The existing knowledge about morbidity in adults with Rubinstein-Taybi syndrome (RTS) is limited and detailed data on their natural history and response to management are needed for optimal care in later life. We formed an international, multidisciplinary working group that developed an accessible questionnaire including key issues about adults with RTS and disseminated this to all known RTS support groups via social media. We report the observations from a cohort of 87 adult individuals of whom 43 had a molecularly confirmed diagnosis. The adult natural history of RTS is defined by prevalent behavioural/psychiatric problems (83%), gastrointestinal problems (73%) that are represented mainly by constipation; and sleep problems (62%) that manifest in a consistent pattern of sleep apnoea, difficulty staying asleep and an increased need for sleep. Furthermore, over than half of the RTS individuals (65%) had skin and adnexa-related problems. Half of the individuals receive multidisciplinary follow-up and required surgery at least once, and most frequently more than once, during adulthood. Our data confirm that adults with RTS enjoy both social and occupational possibilities, show a variegated experience of everyday life but experience a significant morbidity and ongoing medical issues which do not appear to be as coordinated and multidisciplinary managed as in paediatric patients. We highlight the need for optimal care in a multidisciplinary setting including the pivotal role of specialists for adult care.

Management of cardiac aspects in children with Noonan syndrome - results from a European clinical practice survey among paediatric cardiologists.

BACKGROUND: The majority of children with Noonan syndrome (NS) or other diseases from the RASopathy spectrum suffer from congenital heart disease. This study aims to survey cardiac care of this patient cohort within Europe. METHODS: A cross-sectional exploratory survey assessing the treatment and management of patients with NS by paediatric endocrinologists, cardiologists and clinical geneticists was developed. This report details responses of 110 participating paediatric cardiologists from multiple countries. RESULTS: Most paediatric cardiologists responding to the questionnaire were associated with university hospitals, and most treated <10 patients/year with congenital heart disease associated with the NS spectrum. Molecular genetic testing for diagnosis confirmation was initiated by 81%. Half of the respondents reported that patients with NS and congenital heart disease typically present <1y of age, and that a large percentage of affected patients require interventions and pharmacotherapy early in life. A higher proportion of infant presentation and need for pharmacotherapy was reported by respondents from Germany and Sweden than from France and Spain (p = 0.031; p = 0.014; Fisher's exact test). Older age at first presentation was reported more from general hospitals and independent practices than from university hospitals (p = 0.031). The majority of NS patients were followed at specialist centres, but only 37% reported that their institution offered dedicated transition clinic to adult services. Very few NS patients with hypertrophic cardiomyopathy (HCM) were reported to carry implantable cardioverter defibrillators for sudden cardiac death prevention. Uncertainty was evident in regard to growth hormone treatment in patients with NS and co-existing HCM, where 13% considered it not a contra-indication, 24% stated they did not know, but 63% considered HCM either a possible (20%) or definite (15%) contraindication, or a cause for frequent monitoring (28%). Regarding adverse reactions for patients with NS on growth hormone therapy, 5/19 paediatric cardiology respondents reported a total of 12 adverse cardiac events. CONCLUSIONS: Congenital heart disease in patients with NS or other RASopathies is associated with significant morbidity during early life, and specialty centre care is appropriate. More research is needed regarding the use of growth hormone in patients with NS with congenital heart disease, and unmet medical needs have been identified.

European Medical Education Initiative on Noonan syndrome: A clinical practice survey assessing the diagnosis and clinical management of individuals with Noonan syndrome across Europe.

INTRODUCTION: Noonan syndrome (NS) is a rare genetic disorder caused by mutations in genes encoding components of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. Patients with NS exhibit certain characteristic features, including cardiac defects, short stature, distinctive facial appearance, skeletal abnormalities, cognitive deficits, and predisposition to certain cancers. Here, a clinical practice survey was developed to learn more about differences in the diagnosis and management of this disease across Europe. The aim was to identify gaps in the knowledge and management of this rare disorder. MATERIALS AND METHODS: The European Medical Education Initiative on NS, which comprised a group of 10 experts, developed a 60-question clinical practice survey to gather information from European physicians on the diagnosis and clinical management of patients with diseases in the NS phenotypic spectrum. Physicians from three specialities (clinical genetics, paediatric endocrinology, paediatric cardiology) were invited to complete the survey by several national and European societies. Differences in answers provided by respondents between specialities and countries were analysed using contingency tables and the Chi-Squared test for independence. The Friedman's test was used for related samples. RESULTS: Data were analysed from 364 respondents from 20 European countries. Most respondents came from France (21%), Spain (18%), Germany (16%), Italy (15%), United Kingdom (8%) and the Czech Republic (6%). Respondents were distributed evenly across three specialities: clinical genetics (30%), paediatric endocrinology (40%) and paediatric cardiology (30%). Care practices were generally aligned across the countries participating in the survey. Delayed diagnosis did not emerge as a critical issue, but certain unmet needs were identified, including transition of young patients to adult medical services and awareness of family support groups. CONCLUSION: Data collected from this survey provide a comprehensive summary of the diagnosis and clinical management practices for patients with NS across different European countries.

The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder.

De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.

A normative chart for cognitive development in a genetically selected population.

Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cognitive trajectories. Understanding variant-specific cognitive trajectories is clinically important for informed monitoring and identifying patients at risk for comorbid conditions. Here, we demonstrate a variant-specific normative chart for cognitive development for individuals with 22q11.2 deletion syndrome (22q11DS). We used IQ data from 1365 individuals with 22q11DS to construct variant-specific normative charts for cognitive development (Full Scale, Verbal, and Performance IQ). This allowed us to calculate Z-scores for each IQ datapoint. Then, we calculated the change between first and last available IQ assessments (delta Z-IQ-scores) for each individual with longitudinal IQ data (n = 708). We subsequently investigated whether using the variant-specific IQ-Z-scores would decrease required sample size to detect an effect with schizophrenia risk, as compared to standard IQ-scores. The mean Z-IQ-scores for FSIQ, VIQ, and PIQ were close to 0, indicating that participants had IQ-scores as predicted by the normative chart. The mean delta-Z-IQ-scores were equally close to 0, demonstrating a good fit of the normative chart and indicating that, as a group, individuals with 22q11DS show a decline in IQ-scores as they grow into adulthood. Using variant-specific IQ-Z-scores resulted in 30% decrease of required sample size, as compared to the standard IQ-based approach, to detect the association between IQ-decline and schizophrenia (p < 0.01). Our findings suggest that using variant-specific normative IQ data significantly reduces required sample size in a research context, and may facilitate a more clinically informative interpretation of IQ data. This approach allows identification of individuals that deviate from their expected, variant-specific, trajectory. This group may be at increased risk for comorbid conditions, such as schizophrenia in the case of 22q11DS.

Management of growth failure and other endocrine aspects in patients with Noonan syndrome across Europe: A sub-analysis of a European clinical practice survey.

AIM: To date, there is a lack of international guidelines regarding the management of the endocrine features of individuals with Noonan syndrome (NS). The aim was to develop a clinical practice survey to gather information on current treatment and management of these patients across Europe. MATERIALS AND METHODS: A group of 10 experts from three clinical specialities involved in the management of NS patients (clinical geneticists, paediatric endocrinologists, and paediatric cardiologists) developed a 60-question clinical practice survey. The questionnaire was implemented in Survey Monkey and sent to physicians from these three specialities via European/national societies. Contingency tables and the Chi-Squared test for independence were used to examine differences between specialities and countries. RESULTS: In total, responses of 364 specialists (paediatric endocrinologists, 40%; geneticists, 30%; paediatric cardiologists, 30%) from 20 European countries were analysed. While endocrinologists mostly referred to national growth charts for the general population, geneticists mostly referred to NS-specific growth charts. Approximately half of the endocrinologists perform growth hormone (GH) stimulation tests in short patients with low IGF1 levels. Two thirds of endocrinologists begin GH treatment for short patients in early childhood (4-6.9 years), and over half of them selected a threshold of -2 standard deviation score (SDS) according to national growth charts. The main concerns about GH treatment appear to be presence of hypertrophic cardiomyopathy (HCM) (59%), increased risk of malignancy (46%), and limited efficacy (31%). When asked if they consider HCM as a contraindication for GH treatment, one third of respondents skipped this question, and among those who replied, two thirds selected 'cannot answer', suggesting a high level of uncertainty. A total of 21 adverse cardiac responses to GH treatment were reported. Although most respondents had not encountered any malignancy during GH treatment, six malignancies were reported. Finally, about half of the endocrinologists expected a typical final height gain of 1-1.5 SDS with GH treatment. CONCLUSION: This survey describes for the first time the current clinical practice of endocrine aspects of NS across Europe and helps us to identify gaps in the management but also in the knowledge of this genetic disorder.

Further validation and psychometric properties of the Spanish adaptation of the Genetic Counseling Outcome Scale.

Evaluation of clinical genetic services is challenging due to the nature of their interventions. The Genetic Counseling Outcome Scale (GCOS-24), a patient-reported outcome measure, was developed to measure empowerment, an important patient-reported outcome from genetic counseling. Previously, we translated and adapted GCOS-24 for use in Spain, but neither test-retest reliability nor structural and construct validity were assessed at that time. In the present study, we set out to test the reliability and validity of the Spanish adaptation of the GCOS-24 against already validated Spanish language measures of satisfaction with life, anxiety, and health locus of control. 880 patients/families who attended the genetics clinic were invited to participate in a online survey. 201 participants (23%) completed the four questionnaires at the first timepoint, and 59 of these (29%) completed GCOS-24 again the second timepoint, 2-4 weeks later. Test-retest reliability was confirmed, with no significant differences between responses to GCOS-24 at the first and second timepoints and good internal consistency. Convergent validity was confirmed between GCOS-24 and measures of satisfaction with life and anxiety but not with measures of health locus of control. For the structural and construct validation, an exploratory factor analysis was performed. The resulting factorial structure of GCOS-24 consists of 6 factors that accumulate 68% of the variance shared by the 21 items that remained in the model. We applied the factor structure of the three validated measures to the available data and analyzed the correlation between factors of GCOS-24 and the other scales. The results showed significant and consistent correlation with factors of the satisfaction with life and anxiety scales but no significant correlation with internal health locus of control. The use of the Spanish adaptation of GCOS-24 in other genetic clinics in Spain will help to validate it further. This study contributes to the international validation of GCOS-24 to evaluate the quality of genetic counseling in Europe.

De novo missense variants in FBXO11 alter its protein expression and subcellular localization.

Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data, our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs.

Mosaic Variegated Aneuploidy syndrome 2 caused by biallelic variants in CEP57, two new cases and review of the phenotype.

Mosaic Variegated Aneuploidy Syndrome 2 (MVA2; MIM 614114) is a rare autosomal recessive disorder, characterized by mosaic aneuploidies involving multiple chromosomes and tissues, caused by biallelic pathogenic variants in the CEP57 gene. Only 10 patients have been reported to date. We report two additional non related cases born to Moroccan consanguineous parents, carrying the previously described c.915_925dup11 CEP57 homozygous variant. Common features of these 12 cases include growth retardation, typically of prenatal onset, distinctive facial features, endocrine, cardiovascular and skeletal, abnormalities while malignancies have not been reported. This report describes the phenotypical spectrum of MVA2.

Expanding the Phenotypic Spectrum of PAX6 Mutations: From Congenital Cataracts to Nystagmus.

BACKGROUND: Congenital aniridia is a complex ocular disorder, usually associated with severe visual impairment, generally caused by mutations on the PAX6 gene. The clinical phenotype of PAX6 mutations is highly variable, making the genotype-phenotype correlations difficult to establish. METHODS: we describe the phenotype of eight patients from seven unrelated families with confirmed mutations in PAX6, and very different clinical manifestations. RESULTS: Only two patients had the classical aniridia phenotype while the other two presented with aniridia-related manifestations, such as aniridia-related keratopathy or partial aniridia. Congenital cataracts were the main manifestation in three of the patients in this series. All the patients had nystagmus and low visual acuity. CONCLUSIONS: The diagnosis of mild forms of aniridia is challenging, but these patients have a potentially blinding hereditary disease that might present with a more severe phenotype in future generations. Clinicians should be aware of the mild aniridia phenotype and request genetic testing to perform an accurate diagnosis.