Heidi Cope

Phenotypic Homogeneity Provides Increased Support for Linkage on Chromosome 2 in Autistic Disorder

Autistic disorder (AutD) is a neurodevelopmental disorder characterized by significant disturbances in social, communicative, and behavioral functioning. A two-stage genomic screen analysis of 99 families with AutD revealed suggestive evidence for linkage to chromosome 2q (D2S116 nonparametric sib-pair LOD score [MLS] 1.12 at 198 cM). In addition, analysis of linkage disequilibrium for D2S116 showed an allele-specific P value of <.01. Recently, linkage to the same region of 2q was reported in an independent genome screen. This evidence for linkage increased when analysis was restricted to the subset of patients with AutD who had delayed onset (>36 mo) of phrase speech (PSD). We similarly classified our data set of 82 sib pairs with AutD, identifying 45 families with AutD and PSD. Analysis of this PSD subset increased our support for linkage to 2q (MLS 2.86 and HLOD 2.12 for marker D2S116). These data support evidence for a gene on chromosome 2 contributing to risk of AutD, and they suggest that phenotypic homogeneity increases the power to find susceptibility genes for AutD.

SLITRK1 mutations in Trichotillomania

Trichotillomania (TTM) is a chronic behavioral disorder characterized by the irresistible urge to pull out one’s hair, resulting in noticeable hair loss. Clinically, TTM is classified as an impulse-control disorder and believed to belong to the obsessivecompulsive (OCD) spectrum. Tourette’s Syndrome (TS), also belonging to the OCD spectrum, was recently associated with mutations in the slit and trk like 1 (SLITRK1) gene. Abelson et al. identified a frameshift mutation and a 30-UTR micro-RNA binding site variation in three independent TS families. The mother of one proband carried the SLITRK1 mutation and was diagnosed with TTM. Therefore, we hypothesized that sequence variation in SLITRK1 may also contribute to TTM not associated with TS. We have ascertained 44 TTM families in which one or more individuals met DMS-IV criteria for TTM. Self-reports of frequency and duration of hair pulling, related psychiatric symptoms, family history, and blood were obtained from patients and family members under IRB-approved procedures by Duke University Medical Center. We directly re-sequenced the complete SLITRK1 gene in the index cases of 44 TTM families. We identified two novel non-synonymous sequence changes that occurred in two independent TTM subjects of European descent (Figure 1). In family DUK14044, a G > A transition resulted in substitution of arginine for lysine; c.1751G > A, R584K. In a second family (DUK14002), only nine residues downstream, a serine was replaced by glycine; c.1777A >G, S593G (Figure 1b). These sequence variations were not detected in the other TTM cases. Interestingly, both changes occurred within a short distance between the second LRRCT domain and the transmembrane domain of SLITRK1 (Figure 1a). Mutations in this position may be associated with TTM in the absence of TS since the mutations reported by Abelson et al. was in a different part of the protein. We then designed Taqman genotyping assays and screened for the presence of these variations in a sample of 2192 non-TTM Caucasian controls. We controlled for the presence of these variations by using the two TTM patients as positive controls for the assays (primer and probe sequences are available from the

TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone

TMEM231, a functional component of the MKS complex at the ciliary transition zone, is mutated in orofaciodigital syndrome type 3 and Meckel syndrome.

Stratified Whole Genome Linkage Analysis of Chiari Type I Malformation Implicates Known Klippel-Feil Syndrome Genes as Putative Disease Candidates

Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of “CTD-negative” families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3–5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.

Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics.

BackgroundChiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum at the base of the skull, resulting in significant neurologic morbidity. As CMI patients display a high degree of clinical variability and multiple mechanisms have been proposed for tonsillar herniation, it is hypothesized that this heterogeneous disorder is due to multiple genetic and environmental factors. The purpose of the present study was to gain a better understanding of what factors contribute to this heterogeneity by using an unsupervised statistical approach to define disease subtypes within a case-only pediatric population.MethodsA collection of forty-four pediatric CMI patients were ascertained to identify disease subtypes using whole genome expression profiles generated from patient blood and dura mater tissue samples, and radiological data consisting of posterior fossa (PF) morphometrics. Sparse k-means clustering and an extension to accommodate multiple data sources were used to cluster patients into more homogeneous groups using biological and radiological data both individually and collectively.ResultsAll clustering analyses resulted in the significant identification of patient classes, with the pure biological classes derived from patient blood and dura mater samples demonstrating the strongest evidence. Those patient classes were further characterized by identifying enriched biological pathways, as well as correlated cranial base morphological and clinical traits.ConclusionsOur results implicate several strong biological candidates warranting further investigation from the dura expression analysis and also identified a blood gene expression profile corresponding to a global down-regulation in protein synthesis.

Genetic Evaluation and Application of Posterior Cranial Fossa Traits as Endophenotypes for Chiari Type I Malformation

Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the base of the skull. Although cerebellar tonsillar herniation (CTH) is hypothesized to result from an underdeveloped posterior cranial fossa (PF), patients are frequently diagnosed by the extent of CTH without cranial morphometric assessment. We recently completed the largest CMI whole genome qualitative linkage screen to date. Despite an initial lack of statistical evidence, stratified analyses using clinical criteria to reduce heterogeneity resulted in a striking increase in evidence for linkage. The present study focused on the use of cranial base morphometrics to further dissect this heterogeneity and increase power to identify disease genes. We characterized the genetic contribution for a series of PF traits and evaluated the use of heritable, disease‐relevant PF traits in ordered subset analysis (OSA). Consistent with a genetic hypothesis for CMI, much of the PF morphology was found to be heritable and multiple genomic regions were strongly implicated from OSA, including regions on Chromosomes 1 (LOD = 3.07, p = 3 × 10−3) and 22 (LOD = 3.45, p = 6 × 10−5) containing several candidates warranting further investigation. This study underscores the genetic heterogeneity of CMI and the utility of PF traits in CMI genetic studies.

Missing genetic risk in neural tube defects: can exome sequencing yield an insight?

BACKGROUND Neural tube defects (NTD) have a strong genetic component, with up to 70% of variance in human prevalence determined by heritable factors. Although the identification of causal DNA variants by sequencing candidate genes from functionally relevant pathways and model organisms has provided some success, alternative approaches are demanded. METHODS Next generation sequencing platforms are facilitating the production of massive amounts of sequencing data, primarily from the protein coding regions of the genome, at a faster rate and cheaper cost than has previously been possible. These platforms are permitting the identification of variants (de novo, rare, and common) that are drivers of NYTD etiology, and the cost of the approach allows for the screening of increased numbers of affected and unaffected individuals from NTD families and in simplex cases. CONCLUSION The next generation sequencing platforms represent a powerful tool in the armory of the genetics researcher to identify the causal genetic basis of NTDs.

Pregnancy continuation and organizational religious activity following prenatal diagnosis of a lethal fetal defect are associated with improved psychological outcome

The aim of the article is to examine the psychological impact, specifically symptoms of grief, post‐traumatic stress and depression, in women and men who either terminated or continued a pregnancy following prenatal diagnosis of a lethal fetal defect.

Psychosocial Profiles of Parents of Children with Undiagnosed Diseases: Managing Well or Just Managing?

Little is known about the psychosocial profiles of parents who have a child with an undiagnosed chronic illness. The National Institutes of Health Undiagnosed Diseases Network (UDN) evaluates individuals with intractable medical findings, with the objective of discovering the underlying diagnosis. We report on the psychosocial profiles of 50 parents whose children were accepted to one of the network’s clinical sites. Parents completed questionnaires assessing anxiety, depression, coping self-efficacy, and health care empowerment at the beginning of their child’s UDN clinical evaluation. Parents of undiagnosed children had high rates of anxiety and depression (~ 40%), which were significantly inversely correlated with coping self-efficacy, but not with health care empowerment. Coping self-efficacy, depressive, and anxiety symptoms were better in parents with older children and with longer duration of illness. Gender differences were identified, with mothers reporting greater health care engagement than fathers. Overall, our findings suggest that parents of children with undiagnosed diseases maintain positive coping self-efficacy and remain actively engaged in health care and to a lesser degree tolerance for uncertainty, but these come with a high emotional cost to the parents. As the parents’ psychological needs may not be obvious, these should be ascertained and the requisite support provided.

Treatment of profound thrombocytopenia in a patient with Gaucher disease type 1: Is there a role for substrate reduction therapy

The availability of three enzyme replacement therapy (ERT) drugs and two substrate reduction therapy (SRT) drugs to treat Gaucher disease provides an opportunity to tailor therapies to a patients specific clinical concerns. However, there is a gap in the literature regarding individual drug effectiveness in treating particular symptoms and the potential benefits of combination treatment. This report details treatment of a patient with Gaucher disease type 1 whose main clinical concern was profound thrombocytopenia (around 20 × 109/L, normal range: 150–450 × 109/L) with several episodes of bleeding with minimal trauma and bruises. The patient was treated with ERT at doses up to 60 units/kg weekly, with no improvement in platelet levels for 6 years. Subsequently, the patient transitioned to SRT and platelet levels increased almost two fold within the first month, and have remained stable at safe levels (30–60 × 109/L) for almost 2.5 years at the time of publication. This report demonstrates a possible therapeutic benefit of SRT in individual patients who do not meet therapeutic goals in terms of thrombocytopenia after a considerable period on first-line ERT treatment. Oral administration of SRT also improved this patients quality of life allowing discontinuation of weekly ERT infusions, which better accommodated her demanding career and busy lifestyle.