Healthy Parents Research Articles

Autosomal Recessive Congenital Dyserythropoietic Anemia Type III Is Caused By Mutations in the Centralspindlin RACGAP1 Component

▪An autosomal dominant form of congenital dyserythropoietic anemia type III (CDA III) is caused by a missense mutation in the KIF23 gene whose protein product, mitotic kinesin-like protein (MKLP1), is part of the centralspindlin complex involved in cytokinesis. Several case reports suggested the existence of an autosomal recessive inheritance form of CDA III so far not genetically characterized. By means of whole exome sequencing in a Spanish CDA III family with healthy parents, we identified in the male proband a novel homozygous missense mutation p.Pro432Ser in the RACGAP1 gene, which encodes for the RACGAP1 protein (Rac GTPase-activating protein 1, also known as MgcRacGAP or CYK-4), the partner of MKLP1 in the centralspindlin complex. A second CDA III Spanish patient has a different rare and novel homozygous missense mutation, p.Thr220Ala, in the RACGAP1 gene. Both patients presented with macrocytic anemia, aberrant multinucleated erythroblasts in the bone marrow typically seen in CDA III cases, no iron overload and skull defects secondary to severe anemia. Silencing of RACGAP1 using siRNA in HeLa cells mimics the cytokinesis defect observed in the bone marrow of our patients. Both mutations disrupt normal cytokinesis and alter the GTPase balance in patients' cells. We conclude that the autosomal recessive form of CDA type III is caused by mutations in the RACGAP1 gene, encoding for RACGAP1 protein, which is the partner of MKLP1 in the centralspindlin complex critical for cytokinesis and now both proteins are associated with CDA type III. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Child adjustment to parental cancer: A latent profile analysis.

This study aimed to identify latent classes of adjustment in children confronted with parental cancer, based on profiles of traumatic stress symptoms, health-related quality of life (HRQoL), and satisfaction with life. In addition, correlates of classes were examined. Families were recruited through social media, health care providers, and cancer support centers. The sample consisted of 175 children (52% girls, aged M = 11.98, SD = 3.20, range = 6-20 years) from 92 families, including 90 parents with a current or past cancer diagnosis and 71 healthy parents. Children and parents completed self-report questionnaires at home. A latent profile analysis was conducted to identify classes based on child traumatic stress symptoms, HRQoL, and satisfaction with life. Four classes were identified, which were labeled (a) average functioning across domains (64%); (b) high stress, below-average HRQoL and life satisfaction (14%); (c) high stress, below-average HRQoL, and average satisfaction (11%); and (d) high functioning across domains (11%). Child age, parent traumatic stress symptoms, and perceived parental warmth were significantly associated with class membership. Child gender, which parent was diagnosed with cancer, and illness phase were unrelated to class membership. Meaningful subgroups of children can be distinguished based on positive and negative indicators of adjustment to parental cancer. Whereas the majority of children appear to adjust well, 25% of children display high levels of traumatic stress and impaired HRQoL, in some cases combined with low life satisfaction; these children may need specific attention to improve adjustment in the long term. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Children’s charter for lung health

Every child and young person has the right to breathe clean air, with healthy lungs. Preconception, in utero and early life exposures, affect children’s lungs, their lung growth and their...

SUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum

BackgroundJoubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation....

O18 When joints vanish

O18 When joints vanish

Gain-of-function variants in GABRD reveal a novel pathway for neurodevelopmental disorders and epilepsy.

A potential link between GABRD encoding the δ subunit of extrasynaptic GABAA receptors and neurodevelopmental disorders has largely been disregarded due to conflicting conclusions from early studies. However, we identified seven heterozygous missense GABRD variants in 10 patients with neurodevelopmental disorders and generalized epilepsy. One variant occurred in two sibs of healthy parents with presumed somatic mosaicism, another segregated with the disease in three affected family members, and the remaining five occurred de novo in sporadic patients. Electrophysiological measurements were used to determine the functional consequence of the seven missense δ subunit variants in receptor combinations of α1β3δ and α4β2δ GABAA receptors. This was accompanied by analysis of electroclinical phenotypes of the affected individuals. We determined that five of the seven variants caused altered function of the resulting α1β3δ and α4β2δ GABAA receptors. Surprisingly, four of the five variants led to gain-of-function effects, whereas one led to a loss-of-function effect. The stark differences between the gain-of-function and loss-of function effects were mirrored by the clinical phenotypes. Six patients with gain-of-function variants shared common phenotypes: neurodevelopmental disorders with behavioural issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. The EEG showed qualitative analogies among the different gain-of-function variant carriers consisting of focal slowing in the occipital regions often preceding irregular generalized epileptiform discharges, with frontal predominance. In contrast, the one patient carrying a loss-of-function variant had normal intelligence and no seizure history, but has a diagnosis of autism spectrum disorder and suffers from elevated internalizing psychiatric symptoms. We hypothesize that increase in tonic GABA-evoked current levels mediated by δ-containing extrasynaptic GABAA receptors lead to abnormal neurotransmission, which represent a novel mechanism for severe neurodevelopmental disorders. In support of this, the electroclinical findings for the gain-of-function GABRD variants resemble the phenotypic spectrum reported in patients with missense SLC6A1 (GABA uptake transporter) variants. This also indicates that the phenomenon of extrasynaptic receptor overactivity is observed in a broader range of patients with neurodevelopmental disorders, because SLC6A1 loss-of-function variants also lead to overactive extrasynaptic δ-containing GABAA receptors. These findings have implications when selecting potential treatment options, as a substantial portion of available antiseizure medication act by enhancing GABAergic function either directly or indirectly, which could exacerbate symptoms in patients with gain-of-function GABRD variants.

Neurodevelopmental Disorders in Patients With Complex Phenotypes and Potential Complex Genetic Basis Involving Non-Coding Genes, and Double CNVs.

Neurodevelopmental disorders (NDDs) are a heterogeneous class of brain diseases, with a complex genetic basis estimated to account for up to 50% of cases. Nevertheless, genetic diagnostic yield is about 20%. Array-comparative genomic hybridization (array-CGH) is an established first-level diagnostic test able to detect pathogenic copy number variants (CNVs), however, most identified variants remain of uncertain significance (VUS). Failure of interpretation of VUSs may depend on various factors, including complexity of clinical phenotypes and inconsistency of genotype-phenotype correlations. Indeed, although most NDD-associated CNVs are de novo, transmission from unaffected parents to affected children of CNVs with high risk for NDDs has been observed. Moreover, variability of genetic components overlapped by CNVs, such as long non-coding genes, genomic regions with long-range effects, and additive effects of multiple CNVs can make CNV interpretation challenging. We report on 12 patients with complex phenotypes possibly explained by complex genetic mechanisms, including involvement of antisense genes and boundaries of topologically associating domains. Eight among the 12 patients carried two CNVs, either de novo or inherited, respectively, by each of their healthy parents, that could additively contribute to the patients’ phenotype. CNVs overlapped either known NDD-associated or novel candidate genes (PTPRD, BUD13, GLRA3, MIR4465, ABHD4, and WSCD2). Bioinformatic enrichment analyses showed that genes overlapped by the co-occurring CNVs have synergistic roles in biological processes fundamental in neurodevelopment. Double CNVs could concur in producing deleterious effects, according to a two-hit model, thus explaining the patients’ phenotypes and the incomplete penetrance, and variable expressivity, associated with the single variants. Overall, our findings could contribute to the knowledge on clinical and genetic diagnosis of complex forms of NDD.

Newborns physiological differences in low- and high-altitude settings of Ecuador.

Newborns show physiological differences in low- and high-altitude settings of Ecuador; those differences are especially relevant because most important cities in Ecuador are located at high altitude, above 2500 m. This study is an epidemiological, observational, and cross-sectional research performed at San Francisco Hospital in Quito (at 2850 m) and General Hospital in Manta (at 6 m) in the Manabí province. We studied 204 full-term newborns, healthy without any prenatal comorbidities, singleton pregnancy, mestizos, and born of healthy parents born. We found significant differences between the values of red blood cells (RBC), leucocytes, hematocrit, and hemoglobin. There was a difference of 27% more in RBC, 3% at hematocrit, and 0.4 g at hemoglobin in the high-altitude cohort. The leucocyte difference is 1270 cells/µl, which means a difference of 6%. At high-altitude settings, the mean pH was lower than normal values and pO2, pCO2, and HCO3. High-altitude newborns showed RBC of > 4,500,000 cells/µl; leukocytes > 19,000; pO2 ≤ 72 mm Hg; hemoglobin > 17.50 g/dl; and hematocrit > 54%. Both cohorts showed physiological changes of transition to extrauterine life. We observed higher polycythemia, respiratory acidosis, and hypoxemia among high-altitude newborns. High-altitude setting intensifies the physiological changes in hematological and arterial blood gases parameters.

NEW GENES AND DISEASES: EP.301 The alpha2-subunit of the AP2 clathrin adaptor as the causal gene in an atypical myopathy with granulofilamentous inclusions

Clathrin-mediated endocytosis is the best characterized process for the entry of proteins and lipids at the plasma membrane of eukaryotic cells. We have previously shown that at costameres, muscle adhesion and force transmission sites, clathrin recruited by the AP2 adaptor forms flat plaques required for actin and desmin intermediate filament organization. Here, we describe a patient presenting a progressive muscular atrophy with loss of ambulation, complete tetraplegia, ophthalmoplegia, severe scoliosis and lower limb contractures and no cardiac involvement. Electron microscopy of muscle biopsy revealed inclusions composed of filamentous material, vacuoles, honeycomb structures and thin granular material surcharge. This case was classified as a myofibrillar myopathy with granulofilamentous inclusion bodies despite no mutation in DES, FHL1, CRYAB and other usual suspect genes. Whole exome sequencing identified two compound heterozygote single-nucleotide variants in the AP2A2 gene encoding the AP2 a2-subunit. Immunofluorescent labeling on muscle sections displayed intracellular aggregates positive for AP2, clathrin and desmin. Depletion of total AP2 in mouse muscle induced a dystrophic phenotype with severe force loss, subsarcolemmal disorganization, vacuoles and neuromuscular junction defects while specifically depleting AP2 a2-subunit induced small subsarcolemmal disorganization and light neuromuscular junction defects. Lastly, transferrin uptake assays of endocytosis function in the patient fibroblasts showed a decrease in endocytosis rates compared to fibroblasts from his healthy parents. Altogether, our results suggest that AP2A2 could be the causal gene in this family and AP2A2 mutations leading to a severe but atypical myopathy. Mutations in AP2A2 could represent the first case in a wider family of atypical myopathies with desmin inclusions caused by mutations in genes encoding proteins of the endocytosis machinery.

SPTAN1 variants likely cause autosomal recessive complicated hereditary spastic paraplegia.

Heterozygous mutations in SPTAN1 are associated with a broad phenotypical spectrum ranging from axonal neuropathy phenotypes to neurodevelopmental phenotypes with or without epilepsy. Recently, biallelic mutations in SPTAN1 were reported as a potential cause of autosomal recessive pure hereditary spastic paraplegia (HSP). However, no further HSP cases with biallelic SPTAN1 mutations have been reported. Herein, we report the clinical and genetic findings of a patient with complicated HSP likely caused by a novel homozygous SPTAN1 mutation. A patient with complicated HSP from a consanguineous family was recruited. The proband underwent detailed neurological examinations. Homozygosity mapping was performed in the proband and her healthy sister. Whole exome sequencing was performed in the proband. Our patient had early onset motor symptoms with upper motor neuron paralysis and intellectual disability, which is compatible with complicated HSP. Genetic analysis identified a rare homozygous missense mutation in SPTAN1 (c.4162A>G, p.I1388V), which was predicted to be deleterious by in silico tools. Her healthy parents and sister all carried the heterozygous mutation. Our results provided further support for the association of biallelic SPTAN1 variants with HSP and suggested that screening for the SPTAN1 gene should be considered not only in patients with pure HSP but also in patients with complicated HSP.

Short stature is progressive in patients with heterozygous NPR2 mutations

Background NPR2 encodes atrial natriuretic peptide receptor B (ANPRB), a regulator of skeletal growth. Biallelic loss-of-function mutations in NPR2 result in acromesomelic dysplasia Maroteaux type (AMDM; OMIM 602875), while heterozygous mutations may account for 2% to 6% of idiopathic short stature (ISS). Objective Describe the physical proportions and growth characteristics of an extended family with novel NPR2 mutations including members with AMDM, ISS, or normal stature. Design and participants We performed whole exome sequencing in 2 healthy parents and 2 children with AMDM. Detailed genotyping and phenotyping were performed on members of a multigenerational family in an academic medical center. We expressed mutant proteins in mammalian cells and characterized expression and function. Results The sisters with AMDM were compound heterozygotes for missense mutations in the NPR2 gene, a novel p.P93S (maternal) and the previously reported p.R989L (paternal). Both mutant ANPRB proteins were normally expressed in HEK293T cells and exhibited dominant negative effects on wild-type ANPRB catalytic activity. Heterozygous relatives had proportionate short stature (height z-scores -2.06 ± 0.97, median ± SD) compared with their wild-type siblings (-1.37 ± 0.59). Height z-scores progressively and significantly decreased as NPR2-heterozygous children matured, while remaining constant in their wild-type siblings. Conclusions Biallelic NPR2 mutations cause severe skeletal dysplasia (AMDM), whereas heterozygous mutations lead to a subtler phenotype characterized by progressive short stature with by increasing loss of height potential with age.

РОЛЬ СЕМЬИ В СОХРАНЕНИИ ЗДОРОВЬЯ С ПОЗИЦИИ МОЛОДЕЖИ

The article is devoted to the analysis of views of the youth about health, factors contributing to health formation and the role of family in preserving of health. Methodology of work is a survey with electronic Google form. Attitudes and opinion of 430 people, citizens of Russia, mainly of the youngsters aged 18-24, have been studied. There was found that psychological and social components of health are the most important for young people, while the role of physical health in young age is underestimated. The majority of respondents (61,4%) defined healthy family as the one, where there are good sincere relationships between spouses and children. Half of the respondents (51,9%) marked the role of financial status of family in achievement of health. 34,4% of the respondents believe that in a healthy family parents devote much attention to self-development and education of their children. The majority of respondents (88,4%) realize that family is a key factor in formation of healthy behavior and healthy life style. Only half of respondents recognize the positive influence of family on their own health. The results of the study can be applied for development of regional and state programs in the field of public health and health promotion.

Biased Maintenance of Attention on Sad Faces in Clinically Depressed Youth: An Eye-Tracking Study

The role of negative attention biases (AB), central to cognitive models of adult depression, is yet unclear in youth depression. We investigated negative AB in depressed compared to healthy youth and tested whether AB are more pronounced in depressed than at-risk youth. Negative AB was assessed for sad and angry faces with an eye-tracking paradigm [Passive Viewing Task (PVT)] and a behavioural task [Visual Search Task (VST)], comparing three groups of 9–14-year-olds: youth with major depression (MD; n = 32), youth with depressed parents (high-risk; HR; n = 49) and youth with healthy parents (low-risk; LR; n = 42). The PVT revealed MD participants to maintain attention longer on sad faces compared to HR, but not LR participants. This AB correlated positively with depressive symptoms. The VST revealed no group differences. Our results provide preliminary evidence for a negative AB in maintenance of attention on disorder-specific emotional information in depressed compared to at-risk youth.

Chromosomal microarray and exome sequencing in unexplained early infantile epileptic encephalopathies in a highly consanguineous population

Aim To identify genetic causes for early infantile epileptic encephalopathies (EIEE) in Turkish children with mostly consanguineous parents. Methods In a selected EIEE group (N = 59) based on results of nongenetic and initial genetic testing with unexplained etiology, 49 patients underwent array-based comparative genomic hybridization (aCGH) and 49 patients underwent whole exome sequencing (WES) including 39 with negative aCGH results and 10 with WES-only. Results Diagnostic yield of aCGH and WES for pathogenic or likely pathogenic variants was 14.3% and 38.8%, respectively. Including de novo variants of uncertain significance linked to compatible phenotypes, increased the diagnostic yield of WES to 61.2%. Out of 38 positive variants, 18 (47.4%) were novel and 16 (42.1%) were de novo. Twenty-one (56.8%) patients had recessive variants inherited from mostly consanguineous healthy parents (85.7%). Fourteen (37.8%) of patients with diagnostic results had positive variants in established EIEE genes. Seizures started during neonatal period in 32.4% patients. Posture or movement disorders were comorbid with EIEE in 40.5% of diagnosed patients. We identified treatable metabolic disorders in 8.1% of patients and pathogenic variants in genes which support using targeted medicine in 19% of patients. Conclusions Detailed electro-clinical phenotyping led to expansion of some of the known phenotypes with non-neurological and neurological findings in addition to seizures, as well as suggestion of candidate genes (SEC24B, SLC16A2 and PRICKLE2) and a copy number variant (microduplication of Xp21.1p11.4). The high ratio of recessive inheritance could be important for family counseling.

Healthy Parent Carers programme: mixed methods process evaluation and refinement of a health promotion intervention

ObjectivesParent carers of children with special educational needs or disability are at risk of poorer mental and physical health. In response to these needs, we codeveloped the ‘Healthy Parent Carers’...

Information seeking of French parents regarding infant and young child feeding: practices, needs and determinants.

As part of an update of feeding benchmarks targeting children aged 0-3 years, this study aimed to explore parental perceptions, information-seeking practices and needs concerning infant and young child feeding (IYCF) to design an efficient communication strategy. Participants were recruited using the quota sampling to complete an online survey. Effects of parity, child age, prematurity, parental education and financial situation on parents' responses were evaluated separately. France. A nationally representative sample of 1001 parents of children <4 years. Parents whose child had any medical condition affecting feeding (children with medical condition (CMC), 17 %) were considered separately from healthy children's parents. All the healthy children's parents recognised the importance of IYCF for children's health and growth; however, one-third considered the available advice contradictory and not guilt-free. The most used information sources were healthcare professionals (HCP, 81 %), internet (72 %) and parental networks (63 %). The most influential sources (mean influence ± sd) included HCP (7·7 ± 1·7/10), childcare professionals (7·3 ± 1·8/10) and parental networks (6·9 ± 1·8/10). Parents searched for practical tips for implementing IYCF starting when their child was 5 months old. Differences regarding the type of source used by parents with higher v. lower educations were small. Search strategies differed according to parity or child age but not to prematurity. The CMC parents reported slightly different practices and needs. Parents receive information from multiple sources, which can lead to confusion when deciding which advice to follow. A public health communication strategy adapted to the current parental needs should target these various sources.

Four hypotrichosis families with mutations in the gene LSS presenting with and without neurodevelopmental phenotypes.

Four hypotrichosis families with mutations in the gene LSS presenting with and without neurodevelopmental phenotypes.

Healthy Parent Carers: feasibility randomised controlled trial of a peer-led group-based health promotion intervention for parent carers of disabled children

BackgroundParent carers of children with special educational needs or disability are at higher risk of poor mental and physical health. The need for a tailored, peer-led group programme was raised by parent carers, who co-developed the Healthy Parent Carers programme with researchers. This study aimed to test the feasibility of programme delivery in community settings, and the feasibility and acceptability of a randomised controlled trial design.MethodsParticipants were individually randomised with concealed allocation to a structured group programme and access to online resources (intervention), or access to the online resources only (control). Measures of wellbeing and secondary and economic outcomes were collected before randomisation, immediately post-intervention, and 6 months post-intervention. Descriptive statistics on recruitment and attrition, demographics, attendance, and fidelity of intervention delivery were analysed with feedback on the acceptability of the trial design.ResultsOne hundred and ninety-three parent carers expressed an interest in taking part. Ninety-two participants recruited from across six sites were randomised (47 intervention, 45 control). Lead and assistant facilitators were trained and delivered the group sessions. Sixteen (34%) participants in the intervention arm did not attend any sessions, and attendance varied across sites and sessions. One participant withdrew post-randomisation, and 83 (90%) participants completed outcome measures at the six-month follow-up.ConclusionsThe study demonstrated that it was feasible to deliver the programme in community settings. The number of parent carers who expressed interest signifies the need for such a programme and the feasibility of recruiting to a definitive trial. Loss to follow-up was low. Further research is needed to explore ways to reduce barriers to participation in person and assess the feasibility and acceptability of programme content and delivery for more ethnically diverse groups, and potentially using interpreters. Given the Covid-19 pandemic and delivery format feedback, there is also a need to investigate remote or blended delivery strategies. Although the results indicate that a definitive trial is feasible, programme impact would be strengthened through exploration of these uncertainties.Trial registrationISRCTN, ISRCTN15144652, registered on 25 October 2018, ClinicalTrials.gov, NCT03705221, registered on 15 October 2018.

A Novel Germline Compound Heterozygous Mutation of BRCA2 Gene Associated With Familial Peripheral Neuroblastic Tumors in Two Siblings.

ObjectivesTo investigate the genetic variants that are responsible for peripheral neuroblastic tumors (PNTs) oncogenesis in one family case.Materials and MethodsOne family was recruited, including the healthy parents, sister affected by neuroblastoma (NB), and brother who suffered from ganglioneuroma (GN). Whole-genome sequencing (WGS) of germline DNA from all the family members and RNA-seq of tumor RNA from the siblings were performed. Mutants were validated by Sanger sequencing and co-IP was performed to assess the impact of the mutant on chemosensitivity in the SH-SY5Y cell line.ResultsA novel compound heterozygous mutation of BRCA2 was locked as the cause of carcinogenesis. One allele was BRCA2-S871X (stop-gain) from the siblings’ mother, the other was BRCA2-N372H (missense) from their father. This novel compound heterozygous mutations of the BRCA2 gene associated with PNTs by disordering DNA damage and response (DDR) signal pathway. Moreover, chemosensitivity was reduced in the NB cell line due to the BRCA2-N372H mutant.ConclusionIn summary, these results revealed a novel germline compound heterozygous mutation of the BRCA2 gene associated with familial PNTs.

Tetrasomy 18p in one non-identical twin born to healthy parents: A case report

Tetrasomy 18p is an extremely rare disorder with estimated incidence 1:140,000-180,000. The most common clinical presentations include developmental delay, intellectual disability, and several dysmorphic features such as the triangular face, low-set ears, depressed nasal bridge or smooth philtrum. The disease's hallmark is a small supernumerary isochromosome 18p consisting of two copies of the same arm of chromosome 18. Males and females are affected equally. Here, we present the case of 20 months old girl with tetrasomy 18p, the only affected child out of the dizygotic twins born to healthy parents. Routine cytogenetic testing revealed the presence of the marker chromosome in the girl's sample. Combination of Multicolor Banding fluorescent in situ hybridization and array-based Comparative Genomic Hybridization confirmed the isochromosome 18p in this girl. Quantitative Fluorescence PCR determined the maternal origin of the isochromosome 18p. The presented case of tetrasomy18p in one of the non-identical twins supports the hypothesis that tetrasomy 18p arises de novo and are of maternal origin. We conclude that the formation of isochromosome 18p is a random event that can occur in pregnancies of cytogenetically normal parents and maternal age is probably the main risk factor in etiology of the tetrasomy 18p.