An online survey to understand the needs of caregivers of family members with 22q11 deletion syndrome.

BACKGROUND: Most individuals with 22q11.2 deletion syndrome (22q11DS) have multi-system and lifelong needs requiring substantial support. Their primary caregivers are usually family members who dedicate lifelong time and effort to their role. The pressures of their roles can negatively impact caregivers' psychosocial well-being, suggesting a need for additional support for this community who currently have no specialised interventions available. METHOD: This online study surveyed 103 caregivers of family members with 22q11DS to determine the barriers to accessing support that they faced, the kind of support they would value and whether an online intervention could meet their needs. RESULTS: The caregivers indicated that a brief online intervention focused on teaching practical skills and connecting them with a peer network of support would be most valuable. CONCLUSIONS: Future studies are planned that will build on these results by designing and testing online interventions tailored to this community.

Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder.

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

Functional DNA methylation signatures for autism spectrum disorder genomic risk loci: 16p11.2 deletions and CHD8 variants.

BACKGROUND: Autism spectrum disorder (ASD) is a common and etiologically heterogeneous neurodevelopmental disorder. Although many genetic causes have been identified (> 200 ASD-risk genes), no single gene variant accounts for > 1% of all ASD cases. A role for epigenetic mechanisms in ASD etiology is supported by the fact that many ASD-risk genes function as epigenetic regulators and evidence that epigenetic dysregulation can interrupt normal brain development. Gene-specific DNAm profiles have been shown to assist in the interpretation of variants of unknown significance. Therefore, we investigated the epigenome in patients with ASD or two of the most common genomic variants conferring increased risk for ASD. Genome-wide DNA methylation (DNAm) was assessed using the Illumina Infinium HumanMethylation450 and MethylationEPIC arrays in blood from individuals with ASD of heterogeneous, undefined etiology (n = 52), and individuals with 16p11.2 deletions (16p11.2del, n = 9) or pathogenic variants in the chromatin modifier CHD8 (CHD8+/-, n = 7). RESULTS: DNAm patterns did not clearly distinguish heterogeneous ASD cases from controls. However, the homogeneous genetically-defined 16p11.2del and CHD8+/- subgroups each exhibited unique DNAm signatures that distinguished 16p11.2del or CHD8+/- individuals from each other and from heterogeneous ASD and control groups with high sensitivity and specificity. These signatures also classified additional 16p11.2del (n = 9) and CHD8 (n = 13) variants as pathogenic or benign. Our findings that DNAm alterations in each signature target unique genes in relevant biological pathways including neural development support their functional relevance. Furthermore, genes identified in our CHD8+/- DNAm signature in blood overlapped differentially expressed genes in CHD8+/- human-induced pluripotent cell-derived neurons and cerebral organoids from independent studies. CONCLUSIONS: DNAm signatures can provide clinical utility complementary to next-generation sequencing in the interpretation of variants of unknown significance. Our study constitutes a novel approach for ASD risk-associated molecular classification that elucidates the vital cross-talk between genetics and epigenetics in the etiology of ASD.

NSD1 mutations generate a genome-wide DNA methylation signature.

Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1(+/-)-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1(+/-) signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.

Elastin: mutational spectrum in supravalvular aortic stenosis.

Supravalvular aortic stenosis (SVAS) is a congenital narrowing of the ascending aorta which can occur sporadically, as an autosomal dominant condition, or as one component of Williams syndrome. SVAS is caused by translocations, gross deletions and point mutations that disrupt the elastin gene (ELN) on 7q11.23. Functional hemizygosity for elastin is known to be the cause of SVAS in patients with gross chromosomal abnormalities involving ELN. However, the pathogenic mechanisms of point mutations are less clear. One hundred patients with diagnosed SVAS and normal karyotypes were screened for mutations in the elastin gene to further elucidate the molecular pathology of the disorder. Mutations associated with the vascular disease were detected in 35 patients, and included nonsense, frameshift, translation initiation and splice site mutations. The four missense mutations identified are the first of this type to be associated with SVAS. Here we describe the spectrum of mutations occurring in familial and sporadic SVAS and attempt to define the mutational mechanisms involved in SVAS. SVAS shows variable penetrance within families but the progressive nature of the disorder in some cases, makes identification of the molecular lesions important for future preventative treatments.

Velo-cardio-facial syndrome: Implications of microdeletion 22q11 for schizophrenia and mood disorders.

Velo-cardio-facial syndrome (VCFS) is a congenital malformation syndrome with variable phenotypic features that has been associated with chromosomal microdeletion 22q11.2. Psychiatric disorders have been reported to be highly prevalent in individuals with this syndrome, and the objective of this study was to assess the nature and extent of psychopathology among individuals with VCFS. We studied 20 children and adolescents with 22q11 deletions determined by fluorescence in situ hybridization (FISH). Control subjects were 11 nondeleted siblings who were the closest age match to the affected subjects. Both affected and control subjects were assessed using two standardized psychiatric research instruments. The results of this study confirmed the high rate of psychiatric disorders among VCFS subjects (60% of our subjects). Of the specific types of disorders, only mood disorders were significantly more common among VCFS subjects compared to sibling controls, with eight VCFS subjects having mood disorders compared with none of the control subjects (P<0.02). Three affected subjects had schizotypal traits comorbid with a mood disorder. In addition, disruptive behavior disorders were frequently diagnosed among VCFS subjects. Using a dimensional measure of psychopathology, significant differences between VCFS subjects and sibling controls were found on three scales: ADHD (P<0.02), separation anxiety (P<0.02), and depression (P<0.01). VCFS subjects were achieving significantly less well academically and requiring significantly more special educational assistance than sibling controls. Follow-up data were available on two subjects, both of whom had been diagnosed with schizophrenia. Further research on psychopathology in VCFS may provide a model of how a specific genetic defect can lead to the development of psychiatric disorders.

Music skills and the expressive interpretation of music in children with Williams-Beuren syndrome: pitch, rhythm, melodic imagery, phrasing, and musical affect.

This paper studied music in 14 children and adolescents with Williams-Beuren syndrome (WBS), a multi-system neurodevelopmental disorder, and 14 age-matched controls. Five aspects of music were tested. There were two tests of core music domains, pitch discrimination and rhythm discrimination. There were two tests of musical expressiveness, melodic imagery and phrasing. There was one test of musical interpretation, the ability to identify the emotional resonance of a musical excerpt. Music scores were analyzed by means of logistic regressions that modeled outcome (higher or lower music scores) as a function of group membership (WBS or Control) and cognitive age. Compared to age peers, children with WBS had similar levels of musical expressiveness, but were less able to discriminate pitch and rhythm, or to attach a semantic interpretation to emotion in music. Music skill did not vary with cognitive age. Musical strength in individuals with WBS involves not so much formal analytic skill in pitch and rhythm discrimination as a strong engagement with music as a means of expression, play, and, perhaps, improvisation.

The adult phenotype in Costello syndrome.

We report clinical findings in 17 adults with Costello syndrome ranging in age from 16 to 40 years. Two patients in this series have had bladder carcinoma, the only malignancy reported to affect adults with Costello syndrome. Benign tumors included multiple ductal papillomata in two women, and a fourth ventricle mass in one man, thought to be a choroid plexus papilloma. Endocrine problems in this series were osteoporosis, central hypogonadism, and delayed puberty. Other health problems were symptomatic Chiari malformations in three patients. Four patients had adult-onset gastro-esophageal reflux, three of whom had Chiari malformations. Fourteen adults had mild to moderate intellectual disability with three individuals having severe intellectual disability; 15 individuals attained some reading and writing skills and 14 showed ongoing acquisition of new skills into adulthood. On the basis of this data, we recommend that neuro-imaging be considered in adults with Costello syndrome if they develop symptoms suggestive of a Chiari malformation. In the event of pubertal delay, endocrine investigations are indicated and hormone treatment may be required. Bone density assessments should be performed in adults with Costello syndrome, particularly in those with pubertal abnormalities. Screening for microscopic hematuria as a marker for bladder carcinoma may be indicated, although this requires further evaluation.

Counseling and screening for cystic fibrosis in patients with congenital bilateral absence of the vas deferens: Patient perceptions.

Congenital bilateral absence of the vas deferens (CBAVD) occurs in approximately 1.3% of infertile males and is thought to be, in most cases, a primarily genital form of cystic fibrosis (CF). Fourteen males with CBAVD considering microsurgical sperm aspiration from the epididymis (MESA) and in vitro fertilization were seen for genetic counseling and screening for CF. To retrospectively evaluate these patients' perceptions of the counseling and screening information, we conducted structured telephone interviews to assess their recall of information about CF and its impact on their health concerns and reproductive plans. We found that, as the health implications of CF are abstract and not as important to patients as the diagnosis of CBAVD itself, patients tend to view their CF status primarily in terms of their reproductive potential. Retrospective analysis afforded us an opportunity to identify the psychosocial issues of most concern to this unique patient population.

Familial ileal perforation: prenatal diagnosis and postnatal follow-up.

We report sibs (a brother and a sister) who presented prenatally with ultrasound findings of meconium peritonitis and postnatally were found to have perforation of the terminal ileum. The sister presented with fetal ultrasound findings of severe ascites and peritoneal calcifications. She had no prenatal intervention and was born at 38 weeks' gestation. Laparatomy revealed perforation of the terminal ileum with meconium peritonitis. Her post-surgical course was uncomplicated and at 30 months of age her growth and development are normal. Her brother presented prenatally with signs of meconium peritonitis including severe ascites and peritoneal calcifications. Prenatal aspiration of the ascitic fluid was performed and unlike his sister he was born prematurely, was operated on at 8 days, and developed bronchopulmonary dysplasia. He is currently 1 year old and has normal growth and development. The aetiology of the ileal perforation is not known. There were no findings suggesting connective tissue disorder and the aetiology of the intestinal perforation is not known. The occurrence of the same rare abnormality in sibs of different sexes points towards an autosomal recessive disorder.