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Pathogenic variants in the PCDH19 gene are associated with epilepsy, intellectual disability (ID) and behavioural disturbances. Only heterozygous females and mosaic males are affected, likely due to a disease mechanism named cellular interference. Until now, only four affected mosaic male patients have been described in literature. Here, we report five additional male patients, of which four are older than the oldest patient reported so far. All reported patients were selected for genetic testing because of developmental delay and/or epilepsy. Custom-targeted next generation sequencing gene panels for epilepsy genes were used. Clinical data were collected from medical records. All patients were mosaic in blood for likely pathogenic variants in the PCDH19 gene. In most, clinical features were very similar to the female phenotype, with normal development before seizure onset, which occurred between 5 and 10 months of age, clustering of seizures and sensitivity to fever. Four out of five patients had mild to severe ID and behavioural problems. We reaffirm the similarity between male and female PCDH19-related phenotypes, now also in a later phase of the disorder (ages 10-14 years). [ABSTRACT FROM AUTHOR]

Background: Counseling for whole-exome sequencing (WES) could benefit from aligning parents' pre- and post-disclosure attitudes. A few studies have qualitatively compared parents' pre- and post-disclosure attitudes toward receiving WES results for their child in a diagnostic setting. This study explored these attitudes in the context of children with a developmental delay., Methods: Semi-structured interviews were conducted with parents (n = 27) of 16 children undergoing diagnostic WES in trio-analysis, both before and after receiving results., Results: Three key insights emerged. First, the distinction between hoping and expecting was relevant for shaping parents' experiences with receiving results related to the primary indication. Second, parents of young children whose development of autonomous capacities was uncertain sometimes found themselves in a situation resembling a Catch-22 when confronted with decisions about unsolicited findings (UFs): an important reason for consenting to WES was to gain a better picture of how the child might develop, but in order to make responsible choices about UFs, some ideas of their child's development is needed. Third, default opt-ins and opt-outs helped parents fathom new kinds of considerations for accepting or declining UFs in different categories, thereby aiding decision-making., Conclusion: Results from this study are relevant for counseling and policy development., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Massively parallel sequencing techniques, such as whole exome sequencing (WES) and whole genome sequencing (WGS), may reveal unsolicited findings (UFs) unrelated to the diagnostic aim. Such techniques are frequently used for diagnostic purposes in pediatric cases of developmental delay (DD). Yet policy guidelines for informed consent and return of UFs are not well equipped to address specific moral challenges that may arise in these children's situations., Discussion: In previous empirical studies conducted by our research group, we found that it is sometimes uncertain how children with a DD will develop and whether they could come to possess capacities for autonomous decision-making in the future. Parents sometimes felt this brought them into a Catch-22 like situation when confronted with choices about UFs before undergoing WES in trio-analysis (both the parents' and child's DNA are sequenced). An important reason for choosing to consent to WES was to gain more insight into how their child might develop. However, to make responsible choices about receiving or declining knowledge of UFs, some idea of their child's future development of autonomous capacities is needed. This undesirable Catch-22 situation was created by the specific policy configuration in which parents were required to make choices about UFs before being sequencing (trio-analysis). We argue that this finding is relevant for reconfiguring current policies for return of UFs for WES/WGS and propose guidelines that encompass two features. First, the informed consent process ought to be staged. Second, differing guidelines are required for withholding/disclosing a UF in cases of DD appropriate to the level of confidence there is about the child's future developmental of autonomous capacities., Conclusion: When combined with a dynamic consent procedure, these two features of our guidelines could help overcome significant moral challenges that present themselves in the situations of children undergoing genomic sequencing for clarifying a DD., (© 2023. The Author(s).)

Whole-genome sequencing (WGS) can provide valuable health insight for research participants or patients. Opportunities to be sequenced are increasing as direct-to-consumer (DTC) testing becomes more prevalent, but it is still fairly unusual to have been sequenced. We offered WGS to fourteen professionals with pre-existing familiarity with an interest in human genetics - healthcare, science, policy and art. Participants received a hard drive containing their personal sequence data files (.BAM,.gvcf), without further explanation or obligation, to consider how experiencing WGS firsthand might influence their professional attitudes. We performed semi-structured pre- and post-sequencing interviews with each participant to identify key themes that they raised after being sequenced. To evaluate how their experience of the procedure evolved over time, we also conducted a questionnaire to gather their views 3 years after receiving their genomic data. Participants were generally satisfied with the experience (all 14 participants would choose to participate again). They mostly decided to participate out of curiosity (personal) and to learn from the experience (professional). Whereas most participants slightly developed their original perspective on genetic data, a small selection of them radically changed their views over the course of the project. We conclude that personal experience of sequencing provides an interesting alternative perspective for experts involved in leading, planning, implementing or researching genome sequencing services. Moreover, the personal experience may provide professionals with a better understanding of the challenges visitors of the Genetics Clinic of the Future may face., (© 2022. The Author(s).)

The overall diagnostic yield of massively parallel sequencing-based tests in patients with chronic kidney disease (CKD) is 30% for paediatric cases and 6-30% for adult cases. These figures should encourage nephrologists to frequently use genetic testing as a diagnostic means for their patients. However, in reality, several barriers appear to hinder the implementation of massively parallel sequencing-based diagnostics in routine clinical practice. In this article we aim to support the nephrologist to overcome these barriers. After a detailed discussion of the general items that are important to genetic testing in nephrology, namely genetic testing modalities and their indications, clinical information needed for high-quality interpretation of genetic tests, the clinical benefit of genetic testing and genetic counselling, we describe each of these items more specifically for the different groups of genetic kidney diseases and for CKD of unknown origin., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

In a previous study we found that parents of children with developmental delay (DD) favoured acceptance of unsolicited findings (UFs) for medically actionable conditions in childhood, but that preferences diverged for UFs with no medical actionability, or only in adulthood, and regarding carrier status. Sometimes the child's future autonomy formed a reason for withholding UFs for the present, despite an unfavourable prognosis concerning the child's cognitive capabilities. This might be different for children undergoing whole exome sequencing (WES) for reasons other than DD and who are expected to exert future autonomy. This is the focus of the current study. We conducted nine qualitative, semi-structured interviews with parents of children, ages <1-15, after consenting to WES, but prior to feedback of results, and with three adolescent children. Several parents wished to receive any information that might in whatever way be relevant to the health and well-being of their child, and to a lesser extent wished the inclusion of information about non-actionable disorders and information concerning carrier status of autosomal recessive disorders. Although parents understood the rationale behind the centre's UFs disclosure policy, they also felt that they needed this information in order to be able to exert their parental responsibility and take good care of a child still dependent on them. Parents reason from their notion of parental responsibility but are also inclined to take adolescent children's preferences seriously and acknowledge the child's incipient autonomy as a ground for granting an increasing degree of self-determination on the road to adulthood.

We performed a large outcome study at group and individual level in which the goals of genetic counselling were operationalized into cognitive and affective outcomes: empowerment, perceived personal control and anxiety. We then examined which socio-demographic and clinical variables were associated with changes in these outcomes. Data came from 1479 counselees who completed questionnaires (GCOS-18, PPC and STAI) at three time points: before the start of genetic counselling, after the first consultation and after the results of genetic counselling were disclosed. Results showed that at group level empowerment, perceived personal control and anxiety improved significantly after the whole genetic counselling process. Effect-sizes were medium for empowerment and small for the other outcomes. At individual level, 48% of counselees improved in empowerment, 21% in perceived personal control and 17% in anxiety. Around 10% of counselees worsened on all outcomes. Only 'reason for referral' and 'genetic test result' were significantly associated with changes in outcomes. This study demonstrated improvements among counselees in cognitive and affective outcomes after genetic counselling at group level. However, our results also suggest that there are opportunities for improvement at individual level, as many counselees remained stable and some even worsened on all outcomes. Routine outcome monitoring could help to explore the needs of counselees and could help to identify counselees who worsen.

RNA polymerase III (Pol III) is an essential 17-subunit complex responsible for the transcription of small housekeeping RNAs such as transfer RNAs and 5S ribosomal RNA. Biallelic variants in four genes (POLR3A, POLR3B, and POLR1C and POLR3K) encoding Pol III subunits have previously been found in individuals with (neuro-) developmental disorders. In this report, we describe three individuals with biallelic variants in POLR3GL, a gene encoding a Pol III subunit that has not been associated with disease before. Using whole exome sequencing in a monozygotic twin and an unrelated individual, we detected homozygous and compound heterozygous POLR3GL splice acceptor site variants. RNA sequencing confirmed the loss of full-length POLR3GL RNA transcripts in blood samples of the individuals. The phenotypes of the described individuals are mainly characterized by axial endosteal hyperostosis, oligodontia, short stature, and mild facial dysmorphisms. These features largely fit within the spectrum of phenotypes caused by previously described biallelic variants in POLR3A, POLR3B, POLR1C, and POLR3K. These findings further expand the spectrum of POLR3-related disorders and implicate that POLR3GL should be included in genetic testing if such disorders are suspected.

Background: Steroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance., Methods: In an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls., Results: The GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P =1.59×10 -43 ; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F ). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P =1.27×10 -17 ; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6 ., Conclusions: Because CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS., (Copyright © 2019 by the American Society of Nephrology.)

Patient empowerment has been identified as a key outcome goal in genetic counselling, and a patient reported outcome measure (PROM) has been developed to measure empowerment in genetic services: the Genetic Counselling Outcome Scale (GCOS). Here we validate the GCOS for a large and diverse Dutch study sample of 2194 patients referred to two clinical genetic centres for counselling about a wide range of conditions (heart disease, neurological disorders, cancer, congenital syndromes, intellectual disability and prenatal pathology). Our results suggest that the GCOS consists of a hierarchical 6-factor structure, with a main scale for empowerment and six subscales: uncertainty about heredity, hope, negative emotions, knowledge about the condition, knowledge about genetic services and uncertainty about the treatment. Six of the original 24 GCOS items were removed due to low factor loadings and small inter-item correlations. Internal consistency and test-retest reliability of the main scale and most subscales were satisfactory. Convergent validity was confirmed by moderate positive and moderate/strong negative associations between the GCOS main scale and other validated outcome measures. Responsiveness was comparable to that of other validated outcome measures. We saw significant improvement in the GCOS main scale and all the subscales after the first genetic counselling session. This study contributes to the international validation process of the GCOS, with the ultimate goal of using this instrument as a PROM, with empowerment as an outcome measure, to evaluate and improve the quality of genetic counselling in various clinical genetics settings.

A mutation in GDF6 was recently found to underlie a multiple synostoses syndrome. In this report, we describe the second family with GDF6-related multiple synostoses syndrome (SYNS4), caused by a novel c.1287C>A/p.Ser429Arg mutation in GDF6. In addition to synostoses of carpal and/or tarsal bones, at least 6 of 10 affected patients in this family have been diagnosed with mild to moderate hearing loss. In four of them otosclerosis was said to be present, one patient had hearing loss due to severe stapes fixation at the age of 6 years, providing evidence that hearing loss in the GDF6-related multiple synostoses syndrome can be present in childhood. Two others had surgery for stapes fixation at adult age. We hypothesize that, identical to the recently published GDF6-related multiple synostoses family, the p.Ser429Arg mutation also leads to a gain of function. The previously reported c.1330T>A/pTyr444Asn mutation was located in a predicted Noggin and receptor I interacting domain and the gain of function was partly due to resistance of the mutant GDF6 to the BMP-inhibitor Noggin. The results in our family show that mutations predicting to affect the type II receptor interface can lead to a similar phenotype and that otosclerosis presenting in childhood can be part of the GDF6-related multiple synostoses syndrome., (© 2017 Wiley Periodicals, Inc.)

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To detect determinants for photoparoxysmal EEG response (PPR) in SCN1A-related Dravet syndrome (DS)., Methods: Data were studied from nationwide medical histories and EEGs of DS-patients (n=53; 31 males, age 2-19years). Detailed questionnaires on visual stimuli were completed by parents (n=49)., Results: PPR was found in 22 patients (42%; median age 1.25yr), and repeatedly in 17%. PPR (17% of 249 intermittent photic stimulation (IPS)-EEGs) occurred more often with optimal IPS protocols (OR 2.11 [95%CI 1.09-4.13]) and in EEGs showing spontaneous epileptiform abnormalities (OR 5.08 [95%CI 2.05-12.55]). PPR-positive patients tended to be younger at first (p=0.072) and second seizure (p=0.049), showed severe intellectual disability (p=0.042), and had more often spontaneous occipital epileptiform abnormalities (p<0.001). Clinical sensitivity was reported in medical files in 22% of patients and by parents in 43% (self-induction 24%). Clinical or EEG proven visual sensitivity was detected in 65% of cases., Conclusions: Sensitivity to visual stimuli is very common in DS and more often noticed by parents than confirmed by EEG. Detection of PPR improves with repetitive tests using accurate IPS protocols., Significance: Photosensitivity is an important feature in DS and seems to be a marker of the severity of the disorder. Therefore repeated standardized IPS should be encouraged., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Parents' preferences for unsolicited findings (UFs) from diagnostic whole-exome sequencing (WES) for their children remain largely unexplored. Our aim was to gain insight into parental considerations favoring acceptance/decline of UFs pertaining to their child. We conducted 20 qualitative, semistructured interviews with parents (n=34) of children with a developmental delay, aged <1 to 17 years, after consenting to WES, but before feedback of results. Key findings from our study were that all parents favored acceptance of UFs for medically actionable conditions in childhood, but that preferences and considerations diverged for UFs with no medical actionability, or only in adulthood, and regarding carrier-status. Sometimes non-medical utility considerations (considerations of usefulness of knowing UFs, not rooted in (preventive) medical treatment or controls) were given in favor of disclosure of UFs. Sometimes the child's future autonomy formed a reason to withhold UFs at present, despite an unfavorable prognosis concerning the child's cognitive capabilities. Some parents only preferred receiving UFs if these findings were directly related to their reasons for seeking a diagnosis. These findings are essential for developing morally responsible policy and for counseling. Further research should focus on whether considerations of non-medical utility alone can justify disclosure of UFs and whether reasons for seeking a diagnosis place further constraints on what UFs may be returned/withheld. How parents can be aided in contemplating different scenarios regarding their child's future development also deserves further inquiry.

Background: Our clinical observations and two earlier studies indicate familial clustering to be involved in chronic chilblains. Demonstrating phenotypic familial aggregation is a next step to investigate the origin of familial clustering., Objective: This study was initiated to assess evidence for phenotypic familial aggregation in chronic chilblains., Methods: Using a case-control family design in a primary care setting, we computed the familial relative risk of at least one episode of chronic chilblains during life with 95% confidence intervals (CIs). The study population consisted of 192 relatives of 31 case probands (at least one confirmed episode of chronic chilblains). The control population consisted of 178 relatives of 31 sex- and age-matched index controls (no history of chronic chilblains)., Results: The familial relative risk of chronic chilblains was 3.6 (95% CI 1.9-7.3). Additional sensitivity analysis shows similar figures., Conclusion: We demonstrate robust phenotypic familial aggregation in chronic chilblains., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Proximal duplications of chromosome 1q are rare chromosomal abnormalities. Most patients with this condition present with neurological, urogenital, and congenital heart disease and short life expectancy. Mosaicism for trisomy 1q10q23.3 has only been reported once in the literature. Here we discuss a second case: a girl with a postnatal diagnosis of a de novo pure mosaic trisomy 1q1023.3 who has no urogenital or cardiac anomalies.

Objectives: This study aimed to describe seizure precipitants in Dravet syndrome (DS) compared with other epilepsies., Methods: Seizure precipitants as reported in a Dutch cohort of patients with DS with pathogenic SCN1A mutations (n=71) were compared with those of a cohort with childhood epilepsy (n=149) and of a community-based cohort with epilepsy (n=248); for all three Dutch cohorts, the same type of questionnaire was used. Seizure precipitants were categorized as 'fever', 'visual stimuli', 'sleep deprivation', 'stress, including physical exercise', 'auditory stimuli', and 'other'., Results: For 70 (99%) of 71 patients with DS, at least one seizure precipitant was recalled by parents. Seizure precipitants that were reported in more than half of the cohort with DS were as follows: having a fever (97%), having a cold (68%), taking a bath (61%), having acute moments of stress (58%), and engaging in physical exercise (56%). Seizure precipitants freely recalled by parents were often related to ambient warmth or cold-warmth shifts (41%) and to various visual stimuli (18%). Patients with DS had more positive seizure precipitant categories (median 4) compared with the cohort with childhood epilepsy (median 2) and the community-based cohort with epilepsy (median 0) (p<0.001) and showed the highest percentage in each category (all p<0.001). Within the category 'stress, including physical exercise', physical exercise was more often reported to provoke seizures in stress-sensitive patients in the cohort with DS than in the cohort with childhood epilepsy (78% vs. 35%, p<0.001). In the cohort with childhood epilepsy, physical exercise was more often reported in fever-sensitive children than in other children (25% vs. 12%, p=0.042)., Conclusions: Our study shows a high prevalence of a range of seizure precipitants in DS. Our results underscore elevated body temperature as an important seizure precipitant, whether caused by fever, warm bath, ambient warmth, or physical exercise. Knowledge of these seizure precipitants may improve preventive strategies in the otherwise difficult treatment of DS., (Copyright © 2015 Elsevier Inc. All rights reserved.)