Expanding the phenotype of copy number variations involving NR0B1 (DAX1).

46,XY gonadal dysgenesis (GD) is a disorder of sex development due to incomplete gonadal differentiation into testes, resulting in female to ambiguous external genitalia. Duplications at the Xp21.2 locus involving the NR0B1 (DAX1) gene have previously been associated with 46,XY GD. More recently, a complex structural variant not directly involving NR0B1 has been reported in 46,XY GD illustrating that the mechanism of how copy number variants (CNVs) at Xp21.2 may cause 46,XY gonadal dysgenesis is not yet fully understood. Here, we report on three families in which a duplication involving the NR0B1 gene was detected in the context of prenatal screening. This is the first report of duplications involving NR0B1 in three phenotypically normal males in two families. Fertility problems were present in one adult male carrier. The data reported here from an unbiased screening population broaden the phenotype associated with CNVs involving NR0B1, and this may aid clinicians in counseling and decision making in the prenatal context.

Consensus recommendations on altered sensory functioning in Phelan-McDermid syndrome.

Altered sensory functioning is often observed in individuals with SHANK3 related Phelan-McDermid syndrome (PMS). Compared to typically developing individuals and individuals with an autism spectrum disorder, it has been suggested that there are distinctive features of sensory functioning in PMS. More hyporeactivity symptoms and less hyperreactivity and sensory seeking behaviour are seen, particularly in the auditory domain. Hypersensitivity to touch, possible overheating or turning red easily and reduced pain response are often seen. In this paper the current literature on sensory functioning in PMS is reviewed and recommendations for caregivers, based on consensus within the European PMS consortium, are given.

Rare autosomal trisomies detected by non-invasive prenatal testing: an overview of current knowledge.

Non-invasive prenatal testing has been introduced for the detection of Trisomy 13, 18, and 21. Using genome-wide screening also other "rare" autosomal trisomies (RATs) can be detected with a frequency about half the frequency of the common trisomies in the large population-based studies. Large prospective studies and clear clinical guidelines are lacking to provide adequate counseling and management to those who are confronted with a RAT as a healthcare professional or patient. In this review we reviewed the current knowledge of the most common RATs. We compiled clinical relevant parameters such as incidence, meiotic or mitotic origin, the risk of fetal (mosaic) aneuploidy, clinical manifestations of fetal mosaicism for a RAT, the effect of confined placental mosaicism on placental function and the risk of uniparental disomy (UPD). Finally, we identified gaps in the knowledge on RATs and highlight areas of future research. This overview may serve as a first guide for prenatal management for each of these RATs.

The developmental impact of sex chromosome trisomies on emerging executive functions in young children: Evidence from neurocognitive tests and daily life skills.

Sex chromosomal trisomies (SCT) are associated with impairments in executive functions in school-aged children, adolescents, and adults. However, knowledge on preschool development of executive functions is limited but greatly needed to guide early intervention. The current study examined emerging executive functions in young children with SCT. Participants were 72 SCT children and 70 population-based controls, aged 3-7 years, who completed a neurocognitive assessment of both global executive function (MEFS) and verbal executive function skills (NEPSY Word Generation). Caregivers completed the Behavior Rating Inventory of Executive Function (BRIEF) questionnaire to capture real-world behavioral manifestations of impairments in executive functions. Results showed that impairments were significantly more prevalent in SCT than in controls and already present from 3 years, specifically verbal executive functions and working memory. Broader more pronounced impairments were found in older children with SCT. Age was significantly related to executive functions, but specific domains showed different relations with age. For example, deficits in planning and organizing remained evident with older age in SCT whereas it declined with age in controls. Impairments in executive functions were present across different levels of intelligence. Already at an early age, impairments across executive functions should be considered part of the neurodevelopmental profile of SCT, which appear more prominent at later age. Future studies should investigate developmental pathways of executive functions in SCT, given its relevance in cognitive, social, and emotional development. Executive functions should be screened and monitored in children with SCT and could be an important target of preventive intervention.

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin.

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.

Neoplasia in Turner syndrome: a retrospective cohort study in a tertiary referral centre in Belgium.

OBJECTIVES: Patients with Turner syndrome (TS), the most common sex chromosome abnormality in women, can suffer from a variety of well-researched reproductive, cardiovascular, metabolic, and autoimmune comorbidities. Few studies investigate the neoplasia risk. We assessed the general neoplasia risk in TS women, and more specifically, the gonadoblastoma/dysgerminoma risk in the subgroup with Y chromosome mosaicism, and evaluated potential risk factors for neoplasia development, such as karyotype, metabolic and autoimmune comorbidity, and treatment with growth hormone and/or estrogen replacement. DESIGN: 10-year retrospective cohort study in a tertiary referral centre in Belgium. RESULTS: 105 TS women were included (median age 29; range 2-69). Six malignant tumours were detected in 5 (4.8%) patients (SIR = 0.6, 95% CI 0.2-1.0). In addition, 2 benign meningiomas were observed, resulting in 3 (2.9%) tumours of the central nervous system (CNS; SIR = 19.9, 95% CI 4.0-35.8). No breast cancer was noted. Benign neoplasms occurred in 22 women (21.0%), with skin lesions being the most frequent. All patients with Y chromosome mosaicism (n = 9; 8.6%) underwent prophylactic gonadectomy, but gonadoblastoma/dysgerminoma was not detected. A weak association was found between any tumour type and autoimmune comorbidity (r = 0.24; p = 0.02). CONCLUSION: The overall malignancy risk was not increased, but a different pattern of occurrence is apparent, with an increased risk of CNS and skin tumours and a decreased breast cancer risk. Gonadoblastoma/dysgerminoma was not reported. There is a need for centralised multidisciplinary care and prospective research to unravel and predict the neoplasia risk.

Stressed parents, happy parents. An assessment of parenting stress and family quality of life in families with a child with Phelan-McDermid syndrome.

BACKGROUND: Individuals with Phelan-McDermid syndrome (PMS) are characterised by phenotypical traits that can be experienced as challenging by their environment. This study assessed parenting stress and Family Quality of Life (FQOL) in parents of individuals with PMS and identified potential contributing variables. METHOD: Mothers (n = 14) and fathers (n = 13) of individuals with PMS (n = 14; 6 females, 8 males; age 2-37, M = 20, SD = 11.92) completed questionnaires on parenting stress, FQOL, adaptive behaviour and background characteristics. RESULTS: Mothers and fathers experienced high, similar and related levels of parenting stress and FQOL satisfaction. Parenting stress and FQOL satisfaction were inversely related. High and low ratings were retrieved for subscales measuring feelings of parental role restriction and emotional well-being, respectively. The adaptive skills of the individuals with PMS were related to fathers' parenting stress and FQOL satisfaction. CONCLUSIONS: Clinical practice is encouraged to be attentive to family dynamics and grasp opportunities to interact with these dynamics.

Recent developments in Phelan-McDermid syndrome research: an update on cognitive development, communication and psychiatric disorders.

PURPOSE OF REVIEW: The purpose of this review is to summarize the literature on cognitive development, communication, behavioral or psychiatric aspects in Phelan-McDermid syndrome (PMS) and to discuss the clinical implications and recommendations of these summarized findings. RECENT FINDINGS: PMS is often associated with severe communication impairments, behavioral or psychiatric problems and regression. These challenges may adversely affect and impair the quality of life of the individual with PMS and his family. SUMMARY: Individuals with PMS experience intellectual disability, communication and behavioral/psychiatric challenges, such as catatonia, bipolar disorder and regression across the lifespan. Providing appropriate guidance and support to them and their families demands a better understanding of these challenges.

Cancer Surveillance in Healthy Carriers of Germline Pathogenic Variants in BRCA1/2: A Review of Secondary Prevention Guidelines.

Germline pathogenic alterations in the breast cancer susceptibility genes 1 (BRCA1) and 2 (BRCA2) are the most prevalent causes of hereditary breast and ovarian cancer. The increasing trend in proportion of cancer patients undergoing genetic testing, followed by predictive testing in families of new index patients, results in a significant increase of healthy germline BRCA1/2 mutation carriers who are at increased risk for breast, ovarian, and other BRCA-related cancers. This review aims to give an overview of available screening guidelines for female and male carriers of pathogenic or likely pathogenic germline BRCA1/2 variants per cancer type, incorporating malignancies that are more or less recently well correlated with BRCA1/2. We selected guidelines from national/international organizations and/or professional associations that were published or updated between January 1, 2015, and February 1, 2020. In total, 12 guidelines were included. This review reveals several significant discordances between the different guidelines. Optimal surveillance strategies depend on accurate age-specific cancer risk estimates, which are not reliably available for all BRCA-related cancers. Up-to-date national or international consensus guidelines are of utmost importance to harmonize counseling and proposed surveillance strategies for BRCA1/2 carriers.

Deep Phenotyping of Development, Communication and Behaviour in Phelan-McDermid Syndrome.

Phelan-McDermid syndrome (PMS; also referred to as 22q13.3 deletion syndrome) is a congenital condition due to a microdeletion in the SHANK3 gene. Cognitive and communicative deficits as well as behaviour in the autism spectrum are often noticed in affected individuals. The aim of the present study was to obtain a detailed phenotype of the development, communication, and behaviour of 15 individuals with PMS by using both quantitative (questionnaires) and qualitative methods (interviews and observations). In addition, data from the patients' medical records were included. In a subgroup of participants (n = 5), data from a previous study were incorporated to enable a comparison over 2 points in time (longitudinal course). Results indicate a severe to profound level of intellectual disability in all participants, impaired adaptive behaviour, a low level of speech and language, a high incidence of features of autism spectrum disorder (ASD), and a high sensory threshold. Younger individuals (age <18 years) exhibited more challenging behaviour and features of ASD. In older individuals with PMS, a regression across many developmental and adaptive domains was frequently reported and observed. We did not find a relation between the deletion size and the severity of the phenotype. Implications of the findings and recommendations for clinical practice and future research are discussed.

The clinical relevance of intragenic NRXN1 deletions.

BACKGROUND: Intragenic NRXN1 deletions are susceptibility variants for neurodevelopmental disorders; however, their clinical interpretation is often unclear. Therefore, a literature study and an analysis of 43 previously unpublished deletions are provided. METHODS: The literature cohort covered 629 heterozygous NRXN1 deletions: 148 in controls, 341 in probands and 140 in carrier relatives, and was used for clinical hypothesis testing. Exact breakpoint determination was performed for 43 in-house deletions. RESULTS: The prevalence of exonic NRXN1 deletions in controls was ~1/3000 as compared with ~1/800 in patients with neurodevelopmental/neuropsychiatric disorders. The differential distribution of deletions across the gene between controls and probands allowed to distinguish distinct areas within the gene. Exon 6-24 deletions appeared only twice in over 100000 control individuals, had an estimated penetrance for neurodevelopmental disorders of 32.43%, a de novo rate of 50% and segregated mainly with intellectual disability (ID) and schizophrenia. In contrast, exon 1-5 deletions appeared in 20 control individuals, had an estimated penetrance of 12.59%, a de novo rate of 32.5% and were reported with a broad range of neurodevelopmental phenotypes. Exact breakpoint determination revealed six recurrent intron 5 deletions. CONCLUSION: Exon 6-24 deletions have a high penetrance and are mainly associated with ID and schizophrenia. In contrast, the actual contribution of exon 1-5 deletions to a neurodevelopmental/neuropsychiatric disorder in an individual patient and family remains very difficult to assess. To enhance the clinical interpretation, this study provides practical considerations for counselling and an interactive table for comparing a deletion of interest with the available literature data.

Predicting fetoplacental chromosomal mosaicism during non-invasive prenatal testing.

OBJECTIVE: Non-invasive prenatal detection of aneuploidies can be achieved with high accuracy through sequencing of cell-free maternal plasma DNA in the maternal blood plasma. However, false positive and negative non-invasive prenatal testing (NIPT) results remain. Fetoplacental mosaicism is the main cause for false positive and false negative NIPT. We set out to develop a method to detect placental chromosomal mosaicism via genome-wide circulating cell-free maternal plasma DNA screening. METHOD: Aneuploidy detection was combined with fetal fraction determination to enable the detection of placental mosaicism. This pipeline was applied to whole genome sequencing data derived from 19 735 plasma samples. Following an abnormal NIPT, test results were validated by conventional invasive prenatal or postnatal genetic testing. RESULTS: Respectively 3.2% (5/154), 12.8% (5/39), and 13.3% (2/15) of trisomies 21, 18, and 13 were predicted and confirmed to be mosaic. The incidence of other, rare autosomal trisomies was ~0.3% (58/19,735), 45 of which were predicted to be mosaic. Twin pregnancies with discordant fetal genotypes were predicted and confirmed. CONCLUSION: This approach permits the non-invasive detection of fetal autosomal aneuploidies and identifies pregnancies with a high risk of fetoplacental mosaicism. Knowledge about the presence of chromosomal mosaicism in the placenta influences risk estimation, genetic counseling, and improves prenatal management.

Accuracy and clinical value of maternal incidental findings during noninvasive prenatal testing for fetal aneuploidies.

PURPOSE: Genome-wide sequencing of cell-free (cf)DNA of pregnant women aims to detect fetal chromosomal imbalances. Because the largest fraction of cfDNA consists of maternal rather than fetal DNA fragments, maternally derived copy-number variants (CNVs) are also measured. Despite their potential clinical relevance, current analyses do not interpret maternal CNVs. Here, we explore the accuracy and clinical value of maternal CNV analysis. METHODS: Noninvasive prenatal testing was performed by whole-genome shotgun sequencing on plasma samples. Following mapping of the sequencing reads, the landscape of maternal CNVs was charted for 9,882 women using SeqCBS analysis. Recurrent CNVs were validated retrospectively by comparing their incidence with published reports. Nonrecurrent CNVs were prospectively confirmed by array comparative genomic hybridization or fluorescent in situ hybridization analysis on maternal lymphocytes. RESULTS: Consistent with population estimates, 10% nonrecurrent and 0.4% susceptibility CNVs for low-penetrant genomic disorders were identified. Five clinically actionable variants were reported to the pregnant women, including haploinsufficiency of RUNX1, a mosaicism for segmental chromosome 13 deletion, an unbalanced translocation, and two interstitial chromosome X deletions. CONCLUSION: Shotgun sequencing of cfDNA not only enables the detection of fetal aneuploidies but also reveals the presence of maternal CNVs. Some of those variants are clinically actionable or could potentially be harmful for the fetus. Interrogating the maternal CNV landscape can improve overall pregnancy management, and we propose reporting those variants if clinically relevant. The identification and reporting of such CNVs pose novel counseling dilemmas that warrant further discussions and development of societal guidelines.Genet Med 19 3, 306-313.

Copy number variation analysis in adults with catatonia confirms haploinsufficiency of SHANK3 as a predisposing factor.

BACKGROUND: Catatonia is a motor dysregulation syndrome co-occurring with a variety of psychiatric and medical disorders. Response to treatment with benzodiazepines and electroconvulsive therapy suggests a neurobiological background. The genetic etiology however remains largely unexplored. Copy Number Variants (CNV), known to predispose to neurodevelopmental disorders, may play a role in the etiology of catatonia. METHODS: This study is exploring the genetic field of catatonia through CNV analysis in a cohort of psychiatric patients featuring intellectual disability and catatonia. Fifteen adults admitted to a psychiatric inpatient unit and diagnosed with catatonia were selected for array Comparative Genomic Hybridization analysis at 200 kb resolution. We introduced a CNV interpretation algorithm to define detected CNVs as benign, unclassified, likely pathogenic or causal with regard to catatonia. RESULTS: Co-morbid psychiatric diagnoses in these patients were autism, psychotic or mood disorders. Eight patients were found to carry rare CNVs, which could not be classified as benign, comprising 6 duplications and 2 deletions. Microdeletions on 22q13.3, considered causal for catatonia, were detected in 2 patients. Duplications on 16p11.2 and 22q11.2 were previously implicated in psychiatric disorders, but not in catatonia, and were therefore considered likely pathogenic. Driven by the identification of a rare 14q11.2 duplication in one catatonic patient, additional patients with overlapping duplications were gathered to delineate a novel susceptibility locus for intellectual disability and psychiatric disorders on 14q11.2, harboring the gene SUPT16H. Three remaining variants respectively on 2q36.1, 16p13.13 and 17p13.3 were considered variants of unknown significance. CONCLUSION: The identification of catatonia-related copy number changes in this study, underscores the importance of genetic research in patients with catatonia. We confirmed that 22q13.3 deletions, affecting the gene SHANK3, predispose to catatonia, and we uncover 14q11.2 duplications as a novel susceptibility factor for intellectual and psychiatric disorders.

THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability.

Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.

Presenting symptoms in adults with the 22q11 deletion syndrome.

A definitive molecular diagnosis of 22q11 Deletion Syndrome (22q11DS) even if occurring later in life, has important genetic, medical and emotional impact on the patients and their families. The aim of this study is to describe presenting symptoms and age at diagnosis in an adult 22q11DS population. A retrospective study was performed on 65 individuals diagnosed with 22q11DS at adult age. Data were collected on adults referred to the genetic clinic or actively recruited through systematic diagnostic examination in both institutions and a psychiatric unit for intellectually disabled. Presenting symptoms were categorized into seven groups: familial occurrence, intellectual disability, cardiac anomalies, palatal anomalies, facial dysmorphic features, psychiatric problems and 'other' (comprising all other features associated with 22q11DS). Age at diagnosis was defined as the age at which the 22q11.2 deletion was detected by fluorescence in situ hybridization or comparative genomic hybridization. Ascertainment subgroups were different in presenting symptoms and age at diagnosis. Adults were referred to the genetic clinic mainly because of familial occurrence, cardiac defects and psychiatric disorders whereas adults diagnosed in institutions for intellectually disabled presented mainly with moderate to severe intellectual disability and psychotic disorders. Adults diagnosed at the psychiatric unit for intellectually disabled had a variety of psychiatric disorders but none of them had additional physical features. This emphasizes the need to stay alert for presenting symptoms such as conotruncal heart defects or moderate to severe intellectual disability in combination with a history of psychiatric disorders, even in the absence of obvious physical features.

Wolf-Hirschhorn syndrome due to pure and translocation forms of monosomy 4p16.1 → pter.

The aim of this study was to obtain a quantitative definition of Wolf-Hirschhorn syndrome (WHS) through systematic phenotypic analyses in a group of six children with 4p15.32 → pter, 4p15.33 → pter, or 4p16.1 → pter monosomy (considered together as M4p16.1). These results were used for evaluation of the phenotypic effects of a double chromosome imbalance in one child with 4p16.1 → pter monosomy and additional 11q23.3 → qter trisomy. Children with pure M4p16.1 presented with a total of 227 clinical and morphological traits, of which 119 were positive in at least two of them. These traits overlap to a great extent with clinical criteria defining the WHS phenotype. Among the 103 traits identified in the child with unbalanced translocation der(4)t(4;11)(p16.1;q23.3), most clinical and developmental traits (but only 11 morphological) were found to be shared by WHS children with pure M4p16.1 and at least one reported patient with pure 11q trisomy. Forty-six traits of this child corresponded solely to those identified in at least one child with pure M4p16.1. Only five traits of the hybrid phenotype were present in at least one child with pure distal 11q trisomy but in none of the present children with pure M4p16.1. In conclusion, most of the morphological traits of the hybrid phenotype in the child with der(4)t(4;11)(p16.1;q23.3) can be attributed to the M4p16.1, whereas their overlap with those associated with pure distal 11q trisomy is less evident. Phenotype analyses based on the same systematic data acquisition may be useful in understanding the phenotypic effects of different chromosome regions in complex rearrangements. © 2011 Wiley-Liss, Inc.

Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations.

Noonan syndrome (NS) is an autosomal dominant disorder caused by mutations in PTPN11, KRAS, SOS1, and RAF1. We performed SOS1, RAF1, BRAF, MEK1, and MEK2 mutation analysis in a cohort of 102 PTPN11- and KRAS-negative NS patients and found pathogenic SOS1 mutations in 10, RAF1 mutations in 4, and BRAF mutations in 2 patients. Three novel SOS1 mutations were found. One was classified as a rare benign variant and the other remains unclassified. We confirm a high prevalence of pulmonic stenosis and ectodermal abnormalities in SOS1-positive patients. Three patients with SOS1 mutations presented with tumors (embryonal rhabdomyosarcoma, Sertoli cell testis tumor, and granular cell tumors of the skin). One patient with a RAF1 mutation had a lesion suggestive for a giant cell tumor. This is the first report describing different tumor types in NS patients with germ line SOS1 mutations.

Angelman syndrome (AS, MIM 105830).

Angelman syndrome (AS) is a distinct neurogenetic syndrome, first described in 1965. The phenotype is well known in infancy and adulthood, but the clinical features may change with age. The main clinical characteristics include severe mental retardation, epileptic seizures and EEG abnormalilties, neurological problems and distinct facial dysmorphic features. Behavioural problems such as hyperactivity and sleeping problems are reported, although these patients present mostly a happy personality with periods of inappropriate laughter. Different underlying genetic mechanisms may cause AS, with deletion of chromosome 15 as the most frequent cause. Other genetic mechanisms such as paternal uniparental disomy, imprinting defect and mutation in the UBE3A gene are present in smaller groups of patients with AS. As the recurrence risk can be up to 50%, the clinical diagnosis of AS should be confirmed by laboratory tesing, and genetic counselling should be provided. Treatment of seizures, physical therapy or other intervention strategies are helpful to ameliorate the symptoms.