Zuidwester

PurposeARID1B is one of the most frequently mutated genes in intellectual disability cohorts. Thus, far few adult-aged patients with ARID1B-related disorder have been described, which limits our understanding of the disease’s natural history and our ability to counsel patients and their families. MethodsData on patients aged 18+ years with ARID1B-related disorder were collected through an online questionnaire completed by clinicians and parents. ResultsEighty-seven adult patients with ARID1B were included. Cognitive functioning ranged from borderline to severe intellectual disability. Patients identified through the genetic workup of their child were either mosaic or had a variant in exon 1. New clinical features identified in this population are loss of skill (16/64, 25%) and recurrent patella luxation (12/45, 32%). Self-sustainability data showed that 88% (45/51) could eat independently, and 16% (7/45) could travel alone by public transport. Facial photo analysis showed that patients’ photographs taken at different ages clustered consistently, separate from matched controls. ConclusionThe ARID1B spectrum is broad, and as patients age, there is a significant shift in the medical aspects requiring attention. To address the changing medical needs with increasing age, we have formulated recommendations to promote timely intervention in an attempt to mitigate disease progression.

Phenotypic spectrum of SLC6A1-related neurodevelopmental disorders (SLC6A1-NDD) includes intellectual disability (ID), autistic spectrum disorders (ASD), epilepsy, developmental delay, beginning from early infancy or after seizure onset, and other neurological features such as hypotonia and movement disorders. Data on familial phenotypic heterogeneity have been rarely reported, thus in our study we aimed to investigate intrafamilial phenotypic variability in families with SLC6A1 variants. We collected clinical, laboratory and genetic data on 39 individuals, including 17 probands, belonging to 13 families harboring inherited variants of SLC6A1. Data were collected through an international network of Epilepsy and Genetic Centers. Main clinical findings in the whole cohort of 39 subjects were: (a) epilepsy, mainly presenting with generalized seizures, reported in 71% of probands and 36% of siblings or first/second-degree relatives. Within a family, the same epilepsy type (generalized or focal) was observed; (b) ID reported in 100% and in 13% of probands and siblings or first/second-degree relatives, respectively; (c) learning disabilities detected in 28% of the SLC6A1 carriers, all of them were relatives of a proband; (d) around 51% of the whole cohort presented with psychiatric symptoms or behavioral disorders, including 82% of the probands. Out of the 19 patients with psychiatric symptoms, ASD were diagnosed in 40% of them; (e) neurological findings (primarily tremor and speech difficulties) were observed 38.5% of the whole cohort, including 10 probands. Our families harbored 12 different SLC6A1 variants, one was a frameshift, two stop-gain, while the remaining were missense. No genotype-phenotype associations were identified. Our study showed that first-or second-degree relatives presented with a less severe phenotype, featuring mainly mild intellectual and/or learning disabilities, at variance with the probands who suffered from moderate to severe ID, generalized, sometimes intractable, epileptic seizures, behavioral and psychiatric disorders. These findings may suggest that a proportion of individuals with mild SLC6A1-NDD might be missed, in particular those with an older age where genetic testing is not performed. Further studies on intrafamilial phenotypic variability are needed to confirm our results and possibly to expand the phenotypic spectrum of these disorders and benefit genetic counseling.

People with mild to borderline intellectual disabilities face many barriers toward their sexual health. To promote sexual health and overcome these barriers, they need individualized forms of sexuality support and education. To align sexuality support and education insight is needed on their understanding of sexual health. The current paper aims to provide greater insight in what sexual health consists of according to people with mild to borderline intellectual disabilities. Nine people with a mild to borderline intellectual disability participated in a concept mapping procedure, consisting of brainstorming, sorting, and ranking the statements. The resulting clusters and concept map were interpreted by an expert group. Analysis resulted in five clusters which participants considered important for their sexual health. According to people with mild to borderline intellectual disability cluster pertaining to romantic relationships and sexual socialization were the most important. These were followed by clusters on sexual health and lastly sexual selfhood. These results have implications for the development of sexuality support and education, as well as further research.

Genomic microarray may detect susceptibility loci (SL) for neurodevelopmental disorders such as autism and epilepsy, with a yet unquantifiable risk for the fetus. The prenatal disclosure of susceptibility loci is a topic of much debate. Many health care professionals fear that reporting susceptibility loci may put a psychological burden on pregnant couples. It is our policy to disclose prenatal susceptibility loci as we recognize them as actionable for prospective parents. The aim of this report was to evaluate the psychological impact of disclosing a prenatal diagnosis of susceptibility loci. The psychological impact of disclosing susceptibility loci was evaluated in the first patients who received such results. Eight out of 15 women who had a susceptibility locus disclosed and four of their partners consented to share their experiences through a telephonic evaluation (n = 12). Follow-up time ranged from 3 to 15 months after their prenatal test result. The reporting of susceptibility loci was initially ‘shocking’ for five parents while the other seven felt ‘worried’. Ten out of 12 participants indicated they would like to be informed about the susceptibility locus again, two were unsure. Most had no enduring worries. Participants unanimously indicated that pregnant couples should have an individualized pre-test choice about susceptibility loci (non)disclosure. We observed no negative psychological impact with the prenatal diagnosis and disclosure of SL on participants. A key factor in mitigating parental anxiety with SL disclosure appears to be post-test genetic counseling. Our report confirms that pregnant women and their partners prefer an individualized choice regarding the scope of prenatal testing.

The main goal of cytogenetic prenatal diagnosis is to inform prospective parents about the chromosomal status of their fetus. A chromosomal aberration usually causes an abnormal phenotype in childhood. Prenatal whole-genome cytogenetic diagnosis was for a long time dependent on karyotyping, which requires time-consuming cell culturing, has a limited resolution (5–10 Mb) and is dependent on optimal harvesting and chromosome staining conditions. Nowadays, genomic microarray technology allows whole-genome testing at a higher resolution and it can be applied to uncultured fetal material, allowing shorter reporting times when compared with classical cytogenetic techniques. Genomic microarray testing has been recommended for routine postnatal cytogenetics in cases of intellectual disability and/or multiple congenital anomalies1, and for prenatal diagnosis in cases of fetal ultrasound anomalies2. However, its implementation for all indications in prenatal genetic diagnosis is still under discussion3–6. The main arguments against offering prenatal array testing for all indications are the possibility of detecting: (1) CNVs causing well-described clinically significant anomalies not related to the initial indication (unexpected diagnoses); (2) CNVs associated with a variable expressivity and heterogeneity of clinical features, with an as yet unquantifiable chance of an abnormal phenotype if found prenatally (so called susceptibility loci (SL) for neurodevelopmental disorders); and (3) variants of unknown clinical significance (VOUS). Such findings may complicate genetic counseling7–12 and these issues raise further questions, such as which outcomes of genomic microarrays should be reported to pregnant couples? Should they be offered a choice regarding about which possible array outcomes they wish to be informed? Is extensive genetic pretest counseling in every case necessary and feasible in clinical practice? Since this new technology is already present in prenatal clinics, rather than debating whether array testing should be performed for all referrals of invasive cytogenetic prenatal diagnosis, we should instead be discussing how to meet this challenge. In this Editorial, we review the current international status regarding the use of array technology for prenatal diagnosis. We discuss platforms and testing resolution, indications, counseling, (possible problematic) findings and the decision regarding what should be reported to the future parents.