Non-affected Siblings Research Articles

A study of the effect of congenital heart disease on somatic growth by comparing identical twins anthropometric profiles

Abstract Purpose This study seeks to evaluate the impact of congenital heart disease (CHD) on somatic growth while controlling for the influence of other growth-related factors. Method A retrospective cohort study was conducted on identical twins, with one twin having CHD (CHD group) and the other without CHD (non-CHD group). Anthropometric measures, including weight-for-age (WAZ), height-for-age (HAZ), weight-for-height (WHZ), and head-circumference (HCZ) z-scores based on WHO growth standards, were employed, and growth failure was defined by z-scores below -2. Predictive factors of growth failure included gestational age, cyanosis, pulmonary arterial hypertension (PAH), heart failure, and ventricular physiology. Results Anthropometric indices from 41 pairs of twins were analyzed. The CHD group exhibited a significant decline in all growth parameters from the age of 1 year (p < .001). Although the growth disparity between twins lessened over time, the CHD group continued to lag behind the non-CHD group at follow-up (p < .05). Moreover, a higher proportion of the CHD group experienced malnutrition (46.3%) compared to the non-CHD group (7.5%, RR 1.724, 95% CI 1.280 to 2.232, p < .001, at the age of 1). Among disease characteristics, children with cyanosis, PAH, and heart failure displayed a significant decrease in growth z-scores compared to their unaffected twin siblings. However, statistical significance was observed only between weight-for-height z-scores and cyanosis (cyanosis 1.8±1.7 vs acyanosis -0.8±1.4, p = .032). Conclusion Children with CHD exhibited compromised growth compared to their non-affected twin siblings, with no complete catch-up growth observed during the observation period. The heightened prevalence of growth failure in the CHD group emphasizes the increased risk of malnutrition in children with CHD.

Comparison of MicroRNA Levels of 18-60-month-old Autistic Children with Those of Their Siblings and Controls.

The present study aims to compare the levels of 7 microRNAs (mi-RNAs) (mi-RNA-125b, mi-RNA-23a-3p, mi-RNA-146a-5p, mi-RNA-106a, mi-RNA-151a-3p, mi-RNA-28, mi-RNA-125a) in the blood of the preschool children with autism and those of their siblings with healthy controls, and to investigate the association between these mi-RNAs and the severity of autism, behavioral problems, and siblings' autistic traits. A total of 35 children diagnosed with autism spectrum disorder (ASD) at the ages of 18-60 months (patient group), 35 non-affected siblings of the ASD group (sibling group), and 30 control subjects (control group) were involved in the study. The severity of ASD was measured using the Childhood Autism Rating Scale and the Autism Behavior Checklist (ABC). The behavioral problems of the children with ASD were assessed with the Aberrant Behavior Checklist, and the autistic traits of the siblings were assessed using the Autism spectrum screening scale for children. mi-RNA-106a-5p, mi-RNA-151a-3p, and mi-RNA-28-3p were found to be expressed significantly lower in the patient group compared to the control group. There was a significant positive correlation between mi-RNA-23a and the sensory subscale of the ABC. mi-RNA-151a was significantly associated with sound sensitivity and mi-RNA-28 with echolalia. After controlling for age and sex, the differences between groups were disappeared. The present study examined mi-RNAs that have been reported as biomarkers in the literature. Although several symptom clusters are found to be related to certain mi-RNA expression levels, they were not found to be significant in discriminating the patient and healthy groups.

The use of multiplex ARMS-PCR for mutational analysis of beta-globin gene in consanguineous population of KP Pakistan

Purposeß-thalassemia is a hereditary disorder due to mutation in the ß-globin gene on chromosome 11. Out of 200 known ß-globin gene chain mutations recognized, it is better to identify the most common mutation in specific regions and ethnicity for cost-effective molecular diagnosis of this disorder. Therefore, this study aims to practice multiplex-amplification refractory mutation system (ARMS) PCR on patients with thalassemia in Khyber Pakhtunkhwa (KP) to investigate the most common mutations in the ß-globin chain gene.Design/methodology/approachTwenty-two individuals (patients, their parents and non-affected siblings) with signed consent were studied from six consanguineous families of ß-thalassemia. Blood samples were collected for DNA isolation. For the detection of mutations in the ß-globin gene, ARMS-PCR was used. The amplicon was visualized through 2% Agarose Gel.FindingsThe most common mutations among different ethnic groups in the study area residents were Fr 8-9 (+G) and IVS 1-5 (G> C). The prominent enhancing factors for ß-thalassemia are inter-family marriages and lack of awareness.Practical implicationsMultiplex ARMS_PCR is the most valuable technique for assessing multiple mutations in a single reaction tube.Social implicationsDue to extensively found ethnic and regional variations and a high rate of consanguinity, the Pashtun population has a great risk of mutations in their genome. Therefore, ARMS-PCR is a cost-effective mutational diagnostic strategy that can help to control disease burden.Originality/valueLimited studies using ARMS-PCR for mutational analysis in the ß-globin gene are conducted. This study is unique as it targeted consanguineous families of KP Pakistan.

Genome sequencing-based discovery of a novel deep intronic APC pathogenic variant causing exonization

Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome that occurs as a result of germline mutations in the APC gene. Despite a clear clinical diagnosis of FAP, a certain proportion of the APC variants are not readily detectable through conventional genotyping routines. We accomplished genome sequencing in duo of the disease-affected proband and non-affected sibling followed by in silico predictions and a series of RNA-based assays clarifying variant functionality. By prioritizing variants obtained by genome sequencing, we discovered the novel deep intronic alteration APC:c.531 + 1482 A > G that was demonstrated to cause out-of-frame exonization of 56 base pairs from intron 5 of the gene. Further cDNA assays confirmed, that the aberrant splicing event was complete and its splice product was subject to nonsense-mediated decay. Co-segregation was observed between the variant carrier status and the disease phenotype. Cumulative evidence confirmed that APC:c.531 + 1482 A > G is a pathogenic variant causative of the disease.

Prenatal Ultrasound Parameters of Twins With Sagittal Suture Craniosynostosis Question Mechanical Constraint as the Leading Cause.

Multiple pregnancy is a known predisposing factor for sagittal suture synostosis, and intrauterine constraint has been suggested as a potential cause. This study evaluates prenatal images of single and multiple pregnancies of children with sagittal suture synostosis to assess the possible pathogenesis. Prenatal ultrasound data of scaphocephaly twins treated at Erasmus MC was retrieved retrospectively. The head circumference, cephalic index (CI), and biparietal diameter (BPD) were analyzed. Data were compared with the nonaffected sibling, singletons with scaphocephaly, and to general fetal growth reference values. Data of 8 twin pregnancies with 10 cases of scaphocephaly was gathered. For the head circumference no difference was found between affected fetuses and reference values throughout pregnancy. For the BPD a reduced growth was found, compared with control values. The growth curve for the CI of the affected twins is lower from the start and declines over time. When comparing affected fetuses to nonaffected fetuses, the same differences for the BPD and CI were found as compared with controls. No differences in growth parameters were found between the nonaffected siblings and reference values, nor between the affected scaphocephaly twins and singletons with scaphocephaly. Scaphocephaly in twin pregnancy develops early on in pregnancy, similar to singleton pregnancy, making the theory of constraint as a cause less likely. The development of scaphocephaly in twins is likely to be attributed to the same disturbed developmental processes in suture development as in singletons, and not to mechanical constraint.

Siblings’ experiences of having a brother or sister with an eating disorder

IntroductionDespite the huge effect eating disorders (Eds) have on the lives of sufferers and their families there has been little research on the effect an ED has on siblings even though their lives are repeatedly significantly affected by the situation. It is important to gain more insight into the experiences and needs of siblings as the nature and magnitude of the effect of patients EDs on non-affected siblings is mixed in the current research.ObjectivesTo conduct a systematic review allowing an extensive search of the current literature to identify where the current research is lacking. Also, to highlight the need for a greater focus on the effect of EDs on siblings both in research and clinical practice.MethodsA systematic review is being conducted to gain an understanding of the gaps in the literature.ResultsIt is expected that the systematic review will reveal a lack of literature regarding siblings’ experiences of having a brother or sister with an ED. As well as showing the conflicting emotions felt by the siblings, both positive due to the love they feel for their sibling and negative due to the burden they feel.ConclusionsBy raising awareness of the needs of non-affected siblings this research should have a notable impact on their experiences by highlighting the need for specific interventions and support services as well as education about their siblings’ ED.DisclosureNo significant relationships.

The impact of severe rare chronic neurological disease in childhood on the quality of life of families\u2014a study on MLD and PCH2

BackgroundRare and severe neurological disorders in childhood not only heavily affect the life perspective of the patients, but also their caregivers and families. The aim of this study was to investigate the impact of such diseases on the family, especially on the quality of life and life perspectives of parents, but also on the families’ everyday life, based on the model of two diseases which have been well described in recent years with respect to symptoms and course: metachromatic leukodystrophy (MLD) and pontocerebellar hypoplasia type 2 (PCH2). PCH2 is a primary severe developmental disorder, while children with MLD initially develop normally and then progressively deteriorate.MethodsUsing a semi-standardized questionnaire, 43 families with children suffering from MLD (n = 30) or PCH2 (n = 19) reported data on the severity of the illness/symptoms, on family support and the care situation, as well as on the circumstances of non-affected siblings and the parents’ work situation. In addition, the quality of life of parents and general family functioning was assessed using the PedsQL™ Family Impact Module [23]. Results for the latter were compared to published data from families with children without any chronic condition using student’s t-tests for independent samples. Potential factors influencing the PedsQL™ scores were analyzed using Spearman’s rank correlation.ResultsParents of children with MLD and PCH2 reported significantly lower health-related quality of life (HRQOL) compared to parents of healthy children (P < 0.001). Mothers showed significantly poorer HRQOL (P < 0.05) and were significantly more dissatisfied with their professional development (P < 0.05) than fathers, and this was seen in relation to their child's disease. Neither the form of disease (‘primary’ symptomatic PCH2 or ‘secondary’ symptomatic MLD), nor the severity of the child’s illness (in terms of gross motor and speech function) had a specific impact on HRQOL in families. However, the time from diagnosis and advanced symptoms in the terminal disease stage were experienced as especially distressing.ConclusionsThis study illustrates that MLD and PCH2 affect mothers in particular, but also the entire family. This underlines the need for personalized care and counselling of parents and families, especially following diagnosis and during the end stage in a child with a severe, rare chronic neurological disorder.

Plasma lipidomics of monozygotic twins discordant for multiple sclerosis.

Blood biomarkers of multiple sclerosis (MS) can provide a better understanding of pathophysiology and enable disease monitoring. Here, we performed quantitative shotgun lipidomics on the plasma of a unique cohort of 73 monozygotic twins discordant for MS. We analyzed 243 lipid species, evaluated lipid features such as fatty acyl chain length and number of acyl chain double bonds, and detected phospholipids that were significantly altered in the plasma of co‐twins with MS compared to their non‐affected siblings. Strikingly, changes were most prominent in ether phosphatidylethanolamines and ether phosphatidylcholines, suggesting a role for altered lipid signaling in the disease.

Link between childhood trauma and psychotic-like experiences in non-affected siblings of schizophrenia patients: A case-control study.

Prior research has consistently demonstrated a relationship between childhood trauma (CT) exposure and an increased risk of developing psychotic-like experiences (PLE) and disorders. Studying the link between CT and PLE in non-clinical populations with or without genetic risk factors could help elucidate the etiopathogeny of psychotic disorders, by removing the effect of confounding variables related to psychotic-spectrum illnesses. A total of 60 non-affected siblings of patients with schizophrenia and 75 controls (aged 18-35 years) participated in a cross-sectional survey. The Positive Subscale of Community Assessment of Psychotic Experiences (CAPE) and the CT Questionnaire were used. We found no significant difference with regard to positive dimension of the CAPE between the two groups. Siblings have reported higher CAPE negative symptoms scores than controls (27.9 vs 24.2; P= .015), and more emotional abuse and physical neglect during childhood than controls. After controlling for demographic and psychosocial variables, sexual abuse, emotional neglect and physical neglect were positively related to positive psychotic symptoms in the control group, whereas no dimension of CT has been linked to these symptoms in the sibling group. The link between CT and psychosis seems to be complex, not only dependent on genetic vulnerability or early environmental factors shared by siblings of patients with psychotic disorders, but also several other confounding factors, including other psychopathological symptoms. Prevention strategies for individuals at genetic risk of psychosis should pay particular attention to CT as a potential predictor of sub-clinical depression and psychosis.

Enterovirus Neutralizing Antibodies, Monocyte Toll Like Receptors Expression and Interleukin Profiles Are Similar Between Non-affected and Affected Siblings From Long-Term Discordant Type 1 Diabetes Multiplex-Sib Families: The Importance of HLA Background

Enteroviruses are main candidates among environmental agents in the development of type 1 diabetes (T1D). However, the relationship between virus and the immune system response during T1D pathogenesis is heterogeneous. This is an interesting paradigm and the search for answers would help to highlight the role of viral infection in the etiology of T1D. The current data is a cross-sectional study of affected and non-affected siblings from T1D multiplex-sib families to analyze associations among T1D, genetic, islet autoantibodies and markers of innate immunity. We evaluated the prevalence of anti-virus antibodies (Coxsackie B and Echo) and its relationships with human leukocyte antigen (HLA) class II alleles, TLR expression (monocytes), serum cytokine profile and islet β cell autoantibodies in 51 individuals (40 T1D and 11 non-affected siblings) from 20 T1D multiplex-sib families and 54 healthy control subjects. The viral antibody profiles were similar among all groups, except for antibodies against CVB2, which were more prevalent in the non-affected siblings. TLR4 expression was higher in the T1D multiplex-sib family's members than in the control subjects. TLR4 expression showed a positive correlation with CBV2 antibody prevalence (rS: 0.45; P = 0.03), CXCL8 (rS: 0.65, P = 0.002) and TNF-α (rS: 0.5, P = 0.01) serum levels in both groups of T1D multiplex-sib family. Furthermore, within these families, there was a positive correlation between HLA class II alleles associated with high risk for T1D and insulinoma-associated protein 2 autoantibody (IA-2A) positivity (odds ratio: 38.8; P = 0.021). However, the HLA protective haplotypes against T1D prevalence was higher in the non-affected than the affected siblings. This study shows that although the prevalence of viral infection is similar among healthy individuals and members from the T1D multiplex-sib families, the innate immune response is higher in the affected and in the non-affected siblings from these families than in the healthy controls. However, autoimmunity against β-islet cells and an absence of protective HLA alleles were only observed in the T1D multiplex-sib members with clinical disease, supporting the importance of the genetic background in the development of T1D and heterogeneity of the interaction between environmental factors and disease pathogenesis despite the high genetic diversity of the Brazilian population.

Nonsyndromic Craniosynostosis Is Associated with Increased Risk for Psychiatric Disorders.

Craniosynostosis is one of the most common craniofacial malformations demanding surgical treatment in infancy. Data on overall psychiatric morbidity among children with nonsyndromic craniosynostosis remain limited. This study investigated the risk of psychiatric disorders in nonsyndromic craniosynostosis. The authors reviewed a register-based cohort of all individuals born with nonsyndromic craniosynostosis in Sweden between 1973 to 1986 and 1997 to 2012 (n = 1238). The nonsyndromic craniosynostosis cohort was compared with a matched community cohort (n = 12,380) and with unaffected full siblings (n = 1485). The authors investigated the risk of psychiatric disorders, suicide attempts, and suicides by using Cox regression adjusted for perinatal and somatic factors, season and birth year, sex, parental socioeconomic factors, and parental psychiatric disorders. Children with nonsyndromic craniosynostosis had a higher risk of any psychiatric disorder (adjusted Cox-derived hazard ratio, 1.70; 95 percent CI, 1.43 to 2.02), including intellectual disability (adjusted Cox-derived hazard ratio, 4.96; 95 percent CI, 3.20 to 7.70), language disorders (adjusted Cox-derived hazard ratio, 2.36; 95 percent CI, 1.57 to 3.54), neurodevelopmental disorders (adjusted Cox-derived hazard ratio, 1.30; 95 percent CI, 1.01 to 1.69), and other psychiatric disorders (adjusted Cox-derived hazard ratio, 1.43; 95 percent CI, 1.11 to 1.85). Full siblings with nonsyndromic craniosynostosis were more likely, in the crude analyses, to be diagnosed with any psychiatric disorder, including intellectual disability, language disorders, and neurodevelopmental disorders compared with nonaffected siblings. The higher risk for any psychiatric disorder and intellectual disability remained after adjusting for confounders. Children with nonsyndromic craniosynostosis demonstrated higher risks of any psychiatric disorder compared with children without nonsyndromic craniosynostosis. This risk cannot fully be explained by familial influences (i.e., genetic or environmental factors). Risk, III.

Exome Sequencing Reveals Immune Genes as Susceptibility Modifiers in Individuals with \u03b11-Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated to early onset emphysema, mainly imputable to Pi*ZZ genotype. In spite of the serious potential effects, many AATD individuals do not develop emphysema. To identify genes/variants potentially involved in emphysema development we studied 4 AATD families. Each family had at least one affected sibling with emphysema and one non-affected. Whole Exome Sequencing (WES) was performed on genomic DNA isolated from 9 individuals with AATD (4 affected/5 non-affected). Genetic variants confirmed at least in three families were prioritized using QueryOR and network analysis was used to verify enriched pathways. In affected subjects: 14 genes (57% immune-related) segregated in a recessive model and 21 (29% immune-related) in a dominant model. In non-affected subjects: 21 genes (43% immune-related) segregated in a recessive model and 50 (24% immune-related) in a dominant model. In affected siblings immune genes had an activating function, while where immune-suppressing in non-affected siblings involving antigen processing, MHC-I presentation, TCR and PD-1 signalling. This study describes possible genetic susceptibility factors for emphysema development in AATD, and suggests that gene variants involved in regulation of immune homeostasis and maintenance of self-tolerance contribute to the development or suppression of the disease.

Resilience levels among adolescents with ADHD using quantitative measures in a family-design study.

To investigate resilience levels in adolescents with attention-deficit hyperactivity disorder (ADHD) using quantitative measures when compared to their non-affected siblings and controls. We also aimed to investigate the correlation between resilience and depression, anxiety, intelligence quotient (IQ) and socioeconomic status, which may affect resilience levels and be potential confounders. Adolescents (n=45) diagnosed with ADHD referred to an outpatient ADHD clinic, and their siblings without ADHD (n=27), with ages ranging from 12 to 17 years, were interviewed along with their parents using a semi-structured interview (Children's Interview for Psychiatric Syndromes - Parent Version). Intelligence was measured with the Block Design and Vocabulary subtests from the Wechsler Battery. Anxiety and depression were investigated using the Children State-Trait Anxiety Inventory (CSTAI) and the Child Depression Inventory (CDI), respectively. Resilience was investigated using the Resilience Scale. A control group (typically developing adolescents [TDA] and their siblings; n=39) was recruited in another outpatient facility and at two schools using the same methodology. Socioeconomic status and intelligence levels, which may affect resilience, were similar in all groups. Adolescents with ADHD showed lower resilience levels compared to siblings and TDA even when controlled for anxiety and depression levels, which were higher in ADHD. Resilience levels were higher in siblings than in adolescents with ADHD, and lower than in TDA - this last result without statistical significance. In our sample, ADHD in adolescents was associated with lower resilience, even when controlled for confounders often seen in association with the disorder.

A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations.

Causative genetic variants for more than 30 heritable eye disorders in dogs have been reported. For other clinically described eye disorders, the genetic cause is still unclear. We investigated four Golden Retriever litters segregating for highly variable congenital eye malformations. Several affected puppies had unilateral or bilateral retina dysplasia and/or optic nerve hypoplasia. The four litters shared the same father or grandfather suggesting a heritable condition with an autosomal dominant mode of inheritance. The genome of one affected dog was sequenced and compared to 601 control genomes. A heterozygous private nonsense variant, c.487C>T, was found in the SIX6 gene. This variant is predicted to truncate about a third of the open reading frame, p.(Gln163*). We genotyped all available family members and 464 unrelated Golden Retrievers. All three available cases were heterozygous. Five additional close relatives including the common sire were also heterozygous, but did not show any obvious eye phenotypes. The variant was absent from the 464 unrelated Golden Retrievers and 17 non-affected siblings of the cases. The SIX6 protein is a homeobox transcription factor with a known role in eye development. In humans and other species, SIX6 loss of function variants were reported to cause congenital eye malformations. This strongly suggests that the c.487C>T variant detected contributed to the observed eye malformations. We hypothesize that the residual amount of functional SIX6 protein likely to be expressed in heterozygous dogs is sufficient to explain the observed incomplete penetrance and the varying severity of the eye defects in the affected dogs.

Coping styles mediate the association between negative life events and subjective well-being in patients with non-affective psychotic disorders and their siblings

Coping styles are associated with levels of subjective well-being. Negative life events and reduced subjective well-being are more prevalent in patients with psychotic disorders. The aims of the current study were to test a mediation model, with coping styles as potential mediators of the relation between negative life events and subjective well-being in patients with psychotic disorders (N = 259), and aimed to repeat the potential mediation model in patients’ non-affected siblings (N = 309). Data pertains to a subsample of GROUP, a Dutch naturalistic cohort study. The Subjective Well-being under Neuroleptics-20 (SWN-20) scale was used to assess well-being. Coping styles were assessed with the Utrechtse Coping Lijst (UCL). Life events were assessed using an adaptation of the Interview of the Recent Life Event Scale (IRLES). Siblings, but not patients, who experienced negative life events in the previous three year period were more likely to experience a lower well-being. For both groups passive coping styles mediated the relation between negative life events and subjective well-being. Severity of positive, negative or affective symptoms did not change this relationship. Our findings point to a better recognition of copings styles as a therapeutic target to promote well-being and recovery.

Immediate verbal recall and familial dementia risk: population-based study of over 4000 twins

ObjectiveTo investigate the effect of familial risk for dementia on verbal learning by comparing cognitively healthy twins who had demented co-twins with cognitively healthy twins who had cognitively healthy co-twins.Methods4367...

The Functional Connectivity Between the Nucleus Accumbens and the Ventromedial Prefrontal Cortex as an Endophenotype for Bipolar Disorder

BackgroundAlterations in functional connectivity between the nucleus accumbens (NAcc) and frontal cortices have been previously associated with the presence of psychiatric syndromes, including bipolar disorder (BD). Whether these alterations are a consequence or a risk factor for mental disorders remains unresolved. MethodsThis study included 35 patients with BD, 30 nonaffected siblings of patients with BD, and 23 healthy control subjects to probe functional connectivity at rest between NAcc and the rest of the brain in a cross-sectional design. Blood oxygen level–dependent time series at rest from NAcc were used as seed region in a voxelwise correlational analysis. The strength of the correlations found was compared across groups after Fisher’s Z transformation. ResultsWe found increased functional connectivity between the NAcc and the ventromedial prefrontal cortex—comprising mainly the subgenual anterior cingulate—in patients compared with healthy control subjects. Participants at increased genetic risk but yet resilient—nonaffected siblings—showed functional connectivity values midway between the former two groups. ConclusionsOur results are indicative of the potential for the connectivity between NAcc and the ventromedial prefrontal cortex to represent an endophenotype for BD.

Bi-allelic mutations in COL3A1 encoding the ligand to GPR56 are associated with cobblestone-like cortical malformation, white matter changes and cerebellar cysts

Objective: Collagens are one of the major constituents of the pial membrane, which plays a crucial role in neuronal migration and cortical lamination during brain development. Type III procollagen, the chains of which are encoded by COL3A1, is the ligand of the G protein-coupled receptor 56 (GPR56), also known as Adhesion G protein-coupled Receptor G1 (ADGRG1). Heterozygous mutations in COL3A1 result in vascular Ehlers-Danlos syndrome. We show that bi-allelic mutations in COL3A1 are associated with cobblestone-like malformation, white matter changes and cerebellar dysplasia, a phenotype similar to that associated with mutations in GPR56. Methods: Exome analysis was performed in a family consisting of two affected and two non-affected siblings. Brain imaging studies of this family and of two previously reported individuals with bi-allelic mutations in COL3A1 were reviewed. Functional assays were performed on dermal fibroblasts. Results: Exome analysis revealed a novel homozygous variant c.145C>G (p.Pro49Ala) in exon 2 of COL3A1. Brain MRI in the affected siblings as well as in the two previously reported individuals with bi-allelic COL3A1 mutations showed a brain phenotype similar to that associated with mutations in GPR56. Conclusion: Homozygous or compound heterozygous mutations in COL3A1 are associated with cobblestone-like malformation in all three families reported to date. The variability of the phenotype across patients suggests that genetic alterations in distinct domains of type III procollagen can lead to different outcomes. The presence of cobblestone-like malformation in patients with bi-allelic COL3A1 mutations emphasizes the critical role of the type III collagen-GPR56 axis and the pial membrane in the regulation of brain development and cortical lamination.

Bi-allelic variants in COL3A1 encoding the ligand to GPR56 are associated with cobblestone-like cortical malformation, white matter changes and cerebellar cysts

BackgroundCollagens are one of the major constituents of the pial membrane, which plays a crucial role in neuronal migration and cortical lamination during brain development. Type III procollagen, the chains...

Evidence That the Urban Environment Moderates the Level of Familial Clustering of Positive Psychotic Symptoms.

If the shared familial risk factors that predispose to psychotic disorder interact with early-life exposures in the urban environment, familial correlations of psychosis proneness measures should be higher in the exposed environment. We tested the hypothesis that in sib-pairs with one member affected by psychotic disorder, the familial correlation of psychotic experiences, but not depression, negative symptoms, or intelligence quotient (IQ), would be higher if the nonaffected sibling was raised in an urban environment until age 15 years. The sample analyzed consisted of 959 sib-pairs of whom one was affected with psychotic disorder. Lifetime self-reported psychotic and depressive experiences were measured using the self-reported “Community Assessment of Psychic Experiences” (CAPE). In the unadjusted model of the sibling-patient association in CAPE positive symptoms, there was a significant interaction by urban environment (B interaction = 0.079, 95% CI: 0.021 to 0.137, P = .007, n = 828). Stratified analyses revealed a strong sib-pair association in the urban environment (B = 0.077, 95% CI: 0.037 to 0.117, P < .001) and absence of association in the rural environment (B = −0.002, 95% CI: −0.044 to 0.039, P = .920). Associations were not affected after taking into account confounders and outliers, and there was no evidence that sibling associations in IQ, depression, or negative symptoms were moderated by the urban environment. The results agree with previous work indicating that the effects of the genetic and environmental factors that occasion familial clustering of psychotic disorder depend on whether or not an individual spends his early life in an urban environment.