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1.  Hypertension in FMR1 Premutation Males With and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) 
Fragile X-associated tremor ataxia syndrome (FXTAS) is a late onset neurodegenerative disease that affects carriers of the fragile X premutation. This study seeks to assess hypertension risk and susceptibility in male premutation carriers with FXTAS. Although many symptoms and diagnostic criteria have been identified, hypertension risk has not been examined in this population. Data from 92 premutation carriers without FXTAS, 100 premutation carriers with FXTAS, and 186 controls was collected via patient medical interview. Age-adjusted logistic regression analysis was used to examine the relative odds of hypertension. We observed a significantly elevated odds ratio (OR) of hypertension relative to controls for premutation carriers with FXTAS (OR = 3.22, 95% CI: 1.72–6.04; P = 0.0003) among participants over 40-year old. The age-adjusted estimated odds of hypertension in premutation carriers without FXTAS in the over 40-year-old age group was higher compared to controls (OR = 1.61, 95% CI: 0.82–3.16), but was not statistically significant (P = 0.164). Chronic hypertension contributes to cardiovascular complications, dementia, and increased risk of stroke. Our results indicate that the risk of hypertension is significantly elevated in male premutation carriers with FXTAS compared with carriers without FXTAS and controls. Thus, evaluation of hypertension in patients diagnosed with FXTAS should be a routine part of the treatment monitoring and intervention for this disease.
PMCID: PMC3983689  PMID: 22528549
hypertension; FMR1 premutation; fragile X-associated tremor/ataxia syndrome; autonomic disease
2.  Differential PERP Regulation by TP63 Mutants Provides Insight into AEC Pathogenesis 
Ankyloblepharon Ectodermal Dysplasia and Cleft Lip/Palate (AEC) or Hay-Wells Syndrome is an autosomal dominant disorder characterized by a variety of phenotypes in ectodermal derivatives, including severe skin erosions, ankyloblepharon, coarse and wiry hair, scalp dermatitis, and dystrophic nails. AEC is caused by mutations in the gene encoding the TP63 transcription factor, specifically in the Sterile Alpha Motif (SAM) domain. The exact mechanism, however, by which these specific TP63 mutations lead to the observed spectrum of phenotypes is unclear. Analysis of individual TP63 target genes provides a means to understand specific aspects of the phenotypes associated with AEC. PERP is a TP63 target critical for cell-cell adhesion due to its participation in desmosomal adhesion complexes. As PERP null mice display symptoms characteristic of ectodermal dysplasia syndromes, we hypothesized that PERP dysfunction might contribute to AEC. Using luciferase reporter assays, we demonstrate here that PERP induction is in fact compromised with some, but not all, AEC-patient derived TP63 mutants. Through analysis of skin biopsies from AEC patients, we show further that a subset of these display aberrant PERP expression, suggesting the possibility that PERP dysregulation is involved in the pathogenesis of this disease. These findings demonstrate that distinct AEC TP63 mutants can differentially compromise expression of downstream targets, providing a rationale for the variable spectra of symptoms seen in AEC patients. Elucidating how specific TP63 target genes contribute to the pathogenesis of AEC will ultimately help design novel approaches to diagnose and treat AEC.
PMCID: PMC3982294  PMID: 19353588
TP63; mutations; ectodermal dysplasia; PERP; PERP protein; TP53 apoptosis effector protein related to PMP22; skin; biopsy; transgenic mice; Western blotting; immunohistochemistry
3.  Newborn Screening and Cascade Testing for FMR1 Mutations 
We describe an ongoing pilot project in which newborn screening (NBS) for FMR1 mutations and subsequent cascade testing are performed by the MIND Institute at the University of California, Davis Medical Center (UCDMC). To date, out of 3042 newborns initially screened, 44 extended family members have been screened by cascade testing of extended family members once a newborn is identified. 14 newborns (7 males and 7 females) and 27 extended family members (5 males and 22 females) have been identified with FMR1 mutations. Three family histories are discussed in detail, each demonstrating some benefits and risks of NBS and cascade testing for FMR1 mutations in extended family members. While we acknowledge inherent risks, we propose that with genetic counseling, clinical follow-up of identified individuals and cascade testing, newborn screening (NBS) has significant benefits. Treatment for individuals in the extended family who would otherwise not have received treatment can be beneficial. In addition, knowledge of carrier status can lead to lifestyle changes and prophylactic interventions that are likely to reduce the risk of late onset neurological or psychiatric problems in carriers. Also with identification of carrier family members through NBS, reproductive choices become available to those who would not have known that they were at risk to have offspring with fragile X syndrome.
PMCID: PMC3980469  PMID: 23239591
Newborn Screening; FMR1 mutations; Genetic Counseling; Cascade Testing; Premutation
4.  Public Attitudes Regarding a Pilot Study of Newborn Screening for Spinal Muscular Atrophy 
A population-based pilot study of newborns screening for a rare genetic condition, spinal muscular atrophy (SMA), is being conducted with funding from the National Institutes of Health. The first component of the study is to assess the ethical, legal and social implications of population-based pilot studies with a focus on public engagement and parental decision-making for the proposed opt-out approach in this research. We conducted focus groups with members of the general public to ascertain attitudes about the pilot study and acceptability of an opt-out approach in two states, Colorado and Utah, where the pilot screening is being proposed (N = 70). We developed an informational video for the project and showed it to the groups prior to the discussion in order to inform participants about population-based research, newborn screening, permission/consent models, and SMA.
Results indicated support for the conduct of pilot studies that is consistent with the current standard of practice for similar population-based programs. There was support for an opt-out approach for parental decision-making; however there was limited parental knowledge about population-based research, newborn screening and SMA. In general, our participants considered this pilot study to be low risk and of potential benefit to infants and families. The majority of participants were supportive of an opt-out approach with information delivered through various avenues
PMCID: PMC3606635  PMID: 23443997
Newborn screening; population-based research; public health; spinal muscular atrophy; research ethics; focus groups
5.  An unbalanced translocation involving loss of 10q26.2 and gain of 11q25 in a pedigree with autism spectrum disorder and cerebellar juvenile pilocytic astrocytoma 
We report on a pedigree with a pair of brothers each with minor anomalies, developmental delay and autistic-symptoms who share an unbalanced translocation (not detectable by karyotype). The unbalanced translocation involves a 7.1 Mb loss of the terminal portion of 10q, and a 4.2Mb gain of 11q. One of the brothers also developed a cerebellar juvenile pilocytic astrocytoma. The father was found to be a balanced carrier and the couple had a previous miscarriage. We demonstrate that the breakpoint for the triplicated region from chromosome 11 is adjacent to two IgLON genes, namely Neurotrimin (NTM) and Opioid Binding/Cell Adhesion Molecule-like (OPCML). These genes are highly similar neural cell adhesion molecules that have been implicated in synaptogenesis and oncogenesis respectively. The children also have a 10q deletion and are compared to other children with the 10q deletion syndrome which generally does not involve autism spectrum disorders or cancer. Together these data support a role for NTM and OPCML in developmental delay and potentially in cancer susceptibility.
PMCID: PMC3606653  PMID: 23495067
autism spectrum disorder; cerebellar juvenile pilocytic astrocytoma; unbalanced translocation; t(10;11); NTM; OPCML
6.  Postnatal brain and skull growth in an Apert syndrome mouse model 
Craniofacial and neural tissues develop in concert throughout pre- and postnatal growth. FGFR-related craniosynostosis syndromes, such as Apert syndrome (AS), are associated with specific phenotypes involving both the skull and the brain. We analyzed the effects of the FGFR P253R mutation for Apert syndrome using the Fgfr2+/P253R mouse to evaluate the effects of this mutation on these two tissues over the course of development from day of birth (P0) to postnatal day 2 (P2). Three-dimensional magnetic resonance microscopy and computed tomography images were acquired from Fgfr2+/P253R mice and unaffected littermates at P0 (N=28) and P2 (N=23). 3D coordinate data for 23 skull and 15 brain landmarks were statistically compared between groups. Results demonstrate that the Fgfr2+/P253R mice show reduced growth in the facial skeleton and the cerebrum, while the height and width of the neurocranium and caudal regions of the brain show increased growth relative to unaffected littermates. This localized correspondence of differential growth patterns in skull and brain point to their continued interaction through development and suggest that both tissues display divergent postnatal growth patterns relative to unaffected littermates. However, the change in the skull-brain relationship from P0 to P2 implies that each tissue affected by the mutation retains a degree of independence, rather than one tissue directing the development of the other.
PMCID: PMC3606655  PMID: 23495236
Apert syndrome; craniosynostosis; suture; mouse; skull; brain; development; fibroblast growth factor receptor 2
7.  GenTAC Registry Report: Gender Differences Among Individuals with Genetically-Triggered Thoracic Aortic Aneurysm and Dissection 
Previous data suggest women are at increased risk of death from aortic dissection. Therefore, we analyzed data from the GenTAC registry, the NIH-sponsored program that collects information about individuals with genetically-triggered thoracic aortic aneurysms and cardiovascular conditions. We performed cross-sectional analyses in adults with Marfan syndrome (MFS), familial thoracic aortic aneurysm or dissection (FTAAD), bicuspid aortic valve (BAV) with thoracic aortic aneurysm or dissection, and subjects under 50 years of age with thoracic aortic aneurysm or dissection (TAAD<50y). Women comprised 32% of 1449 subjects and were 21% of subjects with BAV, 34% with FTAAD, 22% with TAAD <50y, and 47% with MFS. Thoracic aortic dissections occurred with equal gender frequency yet women with BAV had more extensive dissections. Aortic size was smaller in women but was similar after controlling for BSA. Age at operation for aortic valve dysfunction, aneurysm or dissection did not differ by gender. Multivariate analysis (adjusting for age, BSA, hypertension, study site, diabetes, and subgroup diagnoses) showed that women had fewer total aortic surgeries (OR= 0.65, p < 0.01) and were less likely to receive angiotensin converting enzyme inhibitors (ACEi) (OR=0.68, p < 0.05). As in BAV, other genetically-triggered aortic diseases such as FTAAD and TAAD<50 are more common in males. In women, decreased prevalence of aortic operations and less treatment with ACEi may be due to their smaller absolute aortic diameters. Longitudinal studies are needed to determine if women are at higher risk for adverse events.
PMCID: PMC3606679  PMID: 23444191
Aorta; aneurysm; dissection; gender
8.  Co-occurrence of Autism, Childhood Psychosis, and Intellectual Disability associated with a de novo 3q29 Microdeletion 
Some copy number variants (CNVs) are strongly implicated in both schizophrenia and autism spectrum disorders (ASDs). Childhood-onset schizophrenia (COS) occurs rarely with 0.1 – 1% of all schizophrenia diagnoses manifesting before age 10. 3q29 deletions are associated with both autism and schizophrenia, and are rare - the frequency of the deletion estimated to be 1 in 1750 in developmental disorders. Only one patient with a 3q29 deletion was identified out of the first 1174 families with ASDs included in the Simons Simplex Collection (SSC). We report on detailed clinical findings for this patient with a de novo 3q29 deletion who, as a young child, developed a very rare overlap of symptoms of both autism and early onset psychosis. His ASD was first diagnosed at the age of 4 years and his psychotic symptoms began at 5 years old. This is only the second case reported thus far of this rare event of co-occurring autism and very early onset psychosis in a child with a 3q29 deletion. It is also the earliest case of a child with autism developing comorbid psychosis - manifesting by the age of 5 years.
PMCID: PMC3685481  PMID: 23443968
autism; 3q29; DLG1; PAK2; intellectual disability; psychosis
9.  The Phenotypic Spectrum of ZIC3 Mutations Includes Isolated d-Transposition of the Great Arteries and Double Outlet Right Ventricle 
Disease causing mutations for heterotaxy syndrome were first identified in the X-linked laterality gene, ZIC3. Mutations typically result in males with situs ambiguus and complex congenital heart disease; however affected females and one male with isolated d-transposition of the great arteries (d-TGA) have been reported. We hypothesized that a subset of patients with heart defects common to heterotaxy but without laterality defects would have ZIC3 mutations. We also sought to estimate the prevalence of ZIC3 mutations in sporadic heterotaxy.
Patients with TGA (n=169), double outlet right ventricle (DORV) (n=89), common atrioventricular canal (CAVC) (n= 41) and heterotaxy (n=54) underwent sequencing of ZIC3 exons. We tested 90 patients with tetralogy of Fallot (TOF) to correlate genotype with phenotype. Three potentially disease-related missense mutations were detected: c.49G>T (Gly17Cys) in a female with isolated DORV, c.98C>T (Ala33Val) in a male with isolated d-TGA, and c.841C>T (His281Tyr) in a female with sporadic heterotaxy. We also identified a novel insertion (CPFP333ins) in a family with heterotaxy. All were absent in 200 control patients and the 1000 Genomes Project (n = 629). No significant mutations were found in patients with TOF. Functional studies demonstrated reduced transcriptional activity of the ZIC3 His281Tyr mutant protein.
ZIC3 mutations were rarely identified in isolated DORV and d-TGA suggesting that a subset of DORV and d-TGA may fall within the spectrum of laterality defects. ZIC3 mutations were found in 3.7% of patients with sporadic heterotaxy; therefore testing should be considered in patients with heterotaxy.
PMCID: PMC3707401  PMID: 23427188
Heterotaxy; Situs; Transposition of the great arteries; Double outlet right ventricle; ZIC3
10.  Prenatal testing for Down syndrome: The perspectives of parents of individuals with Down syndrome 
This exploratory, descriptive study examined the views and opinions of parents of individuals with Down syndrome (DS) related to prenatal testing for DS and the use of age-based criteria to determine eligibility for this testing. This survey-based study was designed in collaboration with parents of individuals with DS and the British Columbia-based Lower Mainland Down Syndrome Society (LMDSS). The survey was a 26-item, self-report questionnaire, which was distributed by the LMDSS. Out of the 246 potentially eligible individuals that were mailed surveys, 101 participants returned their completed surveys. The availability of prenatal screening and diagnostic testing for DS was perceived positively by 55.1% and 64.7% of parents, respectively. More than half (60.2%) of participants felt that prenatal diagnostic testing for DS should be available to all pregnant women, regardless of age. In this study, views of Canadian parents of individuals with DS aligned with the prenatal testing policy recently adopted in the USA (whereby any woman, regardless of age or risk factors, can opt for prenatal diagnostic testing) rather than with new Canadian policy (whereby the age for automatic eligibility for diagnostic testing had increased from 35 to 40 years old and more recently is no longer offered on the basis of age-related risks, but on the basis of other risk factors).
PMCID: PMC3958964  PMID: 22354662 CAMSID: cams3092
Down syndrome; prenatal testing; prenatal screening; parent’s attitudes; prenatal diagnosis; policy recommendations; guidelines
11.  Genetic counseling for schizophrenia: a review of referrals to a provincial medical genetics program from 1968–2007 
Recent studies have shown that individuals with schizophrenia and their family members are interested in genetic counseling, but few have received this service. We conducted an exploratory, retrospective study to describe (a) the population of individuals who were referred to the provincial program for genetic counseling for a primary indication of schizophrenia, and (b) trends in number of referrals between 1968 and 2007.
Referrals for a primary indication of schizophrenia were identified through the provincial program database. Charts were reviewed and the following information was recorded: discipline of referring physician, demographics, psychiatric diagnosis, referred individual’s and partner’s (if applicable) family history, and any current pregnancy history. Data were characterized using descriptive statistics.
Between 1968 and 2007, 288 referrals were made for a primary indication of schizophrenia. Most referrals were made: (a) for individuals who had a first-degree family member with schizophrenia, rather than for affected individuals, (b) for preconception counseling, and (c) by family physicians (69%), with only 2% by psychiatrists.
In British Columbia, individuals affected with schizophrenia and their family members are rarely referred for psychiatric genetic counseling. There is a need to identify barriers to psychiatric genetic counseling and develop strategies to improve access.
PMCID: PMC3958978  PMID: 20034078 CAMSID: cams3084
Family History; Genetic Counseling; Psychiatric; Referrals; Schizophrenia
12.  Severe Osteogenesis Imperfecta Caused by a Small In-Frame Deletion in CRTAP 
Mutations of proteins involved in posttranslational modification of collagen type I can cause osteogenesis imperfecta inherited in a recessive pattern. The CRTAP protein is part of a heterotrimeric complex (together with prolyl-3-hydroxylase-1 [P3H1] and cyclophilin B) that 3-hydroxylates the alpha 1 chain of collagen type I at proline residue 986 and plays a collagen chaperon role. CRTAP mutations usually cause severe osteogenesis imperfecta. We report a patient with osteogenesis imperfecta and a homozygous in-frame deletion in CRTAP and a severe form of osteogenesis imperfecta. The girl was born with markedly deformed long bones. Despite intravenous bisphosphonate treatment, she developed multiple vertebral compression fractures and severe scoliosis and at 4 years of age was able to sit only with support. Although CRTAP transcript levels were normal in the patient’s fibroblasts, protein levels of both CRTAP and P3H1 were severely reduced. The degree of 3-hydroxylation at proline residue 986 was also decreased. This report characterizes a patient with a CRTAP small in-frame deletion. We are unaware of prior reports of this finding. We suggest that this deletion affects crucial amino acids that are important for the interaction and/or stabilization of CRTAP and P3H1.
PMCID: PMC3957185  PMID: 21964860
Recessive osteogenesis imperfecta; CRTAP; 3-hydroxylation complex; P3H1
14.  Spectrum of Mutations that cause Distal Arthrogryposis Types 1 and 2B 
The distal arthrogryposis (DA) syndromes are a group of disorders characterized by non-progressive congenital contractures of the limbs. Mutations that cause distal arthrogryposis syndromes have been reported in six genes, each of which encodes a component of the contractile apparatus of skeletal myofibers. However, these reports have usually emanated from gene discovery efforts and thus potentially bias estimates of the frequency of pathogenic mutations at each locus. We characterized the spectrum of pathogenic variants in a cohort of 153 cases of DA1 (n = 48) and DA2B (n = 105). Disease-causing mutations in 56/153 (37%) kindreds including 14/48 (29%) with DA1 and 42/105 (40%) with DA2B were distributed nearly equally across TNNI2, TNNT3, TPM2, and MYH3. In TNNI2, TNNT3, and TPM2 the same mutation caused DA1 in some families and DA2B in others. We found no significant differences among the clinical characteristics of DA by locus or between each locus and DA1 or DA2B. Collectively, the substantial overlap between phenotypic characteristics and spectrum of mutations suggest that DA1 and DA2B should be considered phenotypic extremes of the same disorder.
PMCID: PMC3581718  PMID: 23401156
arthrogryposis; distal arthrogryposis; distal arthrogryposis type 2B; distal arthrogryposis type 1; contracture; clubfoot; congenital vertical talus; congenital limb deformities; congenital foot deformities; congenital hand deformities; congenital upper extremity deformities; congenital lower extremity deformities; musculoskeletal abnormalities; human TNNI2 protein; human TNNT3 protein; human TPM2 protein; human MYH3 polypeptide; troponin I; troponin T; myosin heavy chains; muscle; skeletal muscle
15.  Talocalcaneal Coalition in Muenke Syndrome: Report of a patient, review of the literature in FGFR-related craniosynostoses, and consideration of mechanism 
Muenke syndrome is an autosomal dominant craniosynostosis syndrome resulting from a defining point mutation in the FGFR3 gene. Muenke syndrome is characterized by coronal craniosynostosis (bilateral more often than unilateral), hearing loss, developmental delay and carpal and/or tarsal bone coalition. Tarsal coalition is a distinct feature of Muenke syndrome and has been reported since the initial description of the disorder in the 1990s. Although talocalcaneal coalition is the most common tarsal coalition in the general population, it has never been previously been reported in a patient with Muenke syndrome.
We present a 7-year-old female patient with Muenke syndrome and symptomatic talocalcaneal coalition. She presented at the age of 7 with limping, tenderness and pain in her right foot following a fall and strain of her right foot. She was treated with ibuprofen, shoe inserts, a CAM walker boot and stretching exercises without much improvement in symptoms. A Computed Tomography (CT) scan revealed bilateral talocalcaneal coalitions involving the middle facet. She underwent resection of the talocalcaneal coalitions, remaining pain-free postoperatively with an improvement in her range of motion, gait and mobility.
This report expands the phenotype of tarsal coalition in Muenke syndrome to include talocalcaneal coalition. A literature review revealed a high incidence of tarsal coalition in all FGFR related craniosynostosis syndromes when compared to the general population, a difference that is statistically significant. The most common articulation involved in all syndromic craniosynostoses associated with FGFR mutations is the calcaneocuboid articulation.
PMCID: PMC3581720  PMID: 23378035
Muenke syndrome; FGFR3 craniosynostosis; Tarsal fusion craniosynostosis; Tarsal coalition craniosynostosis; Talocalcaneal coalition; Syndromic craniosynostosis tarsal coalition; FGFR craniosynostosis tarsal fusion; Muenke syndrome tarsal fusion; Muenke syndrome tarsal coalition; The feet Muenke syndrome
16.  Novel FREM1 Mutations Expand the Phenotypic Spectrum Associated with Manitoba-Oculo-Tricho-Anal (MOTA) Syndrome and Bifid Nose Renal Agenesis Anorectal Malformations (BNAR) Syndrome 
Loss of function mutations in FREM1 have been demonstrated in Manitoba-oculo-tricho-anal (MOTA) syndrome and Bifid Nose Renal Agenesis and Anorectal malformations (BNAR) syndrome, but the wider phenotypic spectrum that is associated with FREM1 mutations remains to be defined. We screened three probands with phenotypic features of MOTA syndrome. In one severely affected infant who was diagnosed with MOTA syndrome because of bilateral eyelid colobomas, a bifid nasal tip, hydrometrocolpos and vaginal atresia, we found two nonsense mutations that likely result in complete loss of FREM1 function. This infant also had renal dysplasia, a finding more consistent with BNAR syndrome. Another male who was homozygous for a novel stop mutation had a extensive eyelid colobomas, corneopalpebral synechiae and unilateral renal agenesis. A third male child diagnosed with MOTA syndrome because of corneopalpebral synechiae and eyelid colobomas had a homozygous splice site mutation in FREM1. These cases illustrate that disruption of the FREM1 gene can produce a spectrum of clinical manifestations encompassing the previously described MOTA and BNAR syndromes, and that features of both syndromes may be seen in the same individual. The phenotype of FREM1-related disorders is thus more pleiotropic than for MOTA and BNAR syndrome alone and more closely resembles the widespread clinical involvement seen with Fraser syndrome. Moreover, our first case demonstrates that vaginal atresia may be a feature of FREM1-related disorders.
PMCID: PMC3581754  PMID: 23401257
Manitoba-oculo-tricho-anal (MOTA) syndrome; Bifid nose renal agenesis anorectal malformations (BNAR) syndrome; FREM1; vaginal atresia
17.  Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: A report from the National Down Syndrome Project 
Both a lack of maternal folic acid supplementation and the presence of genetic variants that reduce enzyme activity in folate pathway genes have been linked to meiotic nondisjunction of chromosome 21; however, the findings in this area of research have been inconsistent. To better understand these inconsistencies, we asked whether maternal use of a folic acid-containing supplement before conception reduces risk for chromosome 21 nondisjunction. Using questionnaire data from the National Down Syndrome Project, a population-based case-control study, we compared the use of folic acid-containing supplements among mothers of infants with full trisomy 21 due to maternal nondisjunction (n=702) and mothers of infants born with no major birth defects (n=983). Using logistic regression, adjusting for maternal age, race/ethnicity, and infant age at maternal interview, we found no evidence of an association between lack of folic acid supplementation and maternal nondisjunction among all case mothers (OR=1.16; 95% CI: 0.90–1.48). In analyses stratified by meiotic stage and maternal age (<35 years or ≥ 35 years), we found an association among older mothers experiencing meiosis II nondisjunction errors (OR=2.00; 95% CI: 1.08–3.71). These data suggest that lack of folic acid supplementation may be associated specifically with MII errors in the aging oocyte. If confirmed, these results could account for inconsistencies among previous studies, as each study sample may vary by maternal age structure and proportion of meiotic errors.
PMCID: PMC3607196  PMID: 23401135
Down syndrome; Trisomy 21; Aneuploidy; Nondisjunction; Chromosome segregation; Folic acid; Meiosis
18.  Linking MECP2 and pain sensitivity: the example of Rett syndrome 
Recent animal studies suggest links between MeCP2 function and sensitivity to pain. This study investigated the nature and prevalence of atypical pain responses in Rett syndrome and their relationships with specific MECP2 mutations. Families enrolled in the Australian Rett Syndrome Database (ARSD) and InterRett database participated in this study. Cases with a known MECP2 pathogenic mutation, whose families had completed a questionnaire on registration and had answered questions on pain sensitivity were included (n=646). Logistic regression was used to analyze relationships between the atypical pain responses and genotype. Descriptions of decreased pain sensitivity were content analyzed. The prevalence estimate of reporting an abnormal pain response was 75.2% and a decreased sensitivity to pain was 65.0% in the population-based ARSD. Families of ARSD and InterRett subjects with a C-terminal (OR 2.6; 95% CI 0.8–8.0), p.R168X (OR 2.1; 95% CI 0.7–6.1) or p.R306C (OR 2.7; 95% CI 0.8–9.6) mutation were more likely to report decreased sensitivity to pain. Parents and carers described decreased and delayed responses in situations judged likely to cause pain such as injections, falls, trauma and burns. This study has provided the first precise estimate of the prevalence of abnormal sensitivity to pain in Rett syndrome but specific relationships with genotype are not yet clear. Clinical practice should include a low threshold for the clinical assessment of potential injuries in Rett syndrome.
PMCID: PMC3913729  PMID: 20425824
MCEP2; pain insensitivity; Rett syndrome
20.  Timing of Diagnosis of 47,XXY and 48,XXYY: A Survey of Parent Experiences 
47,XXY/Klinefelter syndrome is the most common sex chromosomal aneuploidy, yet 64% of males with this condition go undiagnosed. 48,XXYY is less common and there is less known about the diagnosis. The objective of this study is to describe the diagnosis experiences of parents of males with 47,XXY and 48,XXYY. Parents of 89 males with 47,XXY and 76 males with 48,XXYY completed a survey that gathered data about their experiences leading to a diagnosis, including the current age of the child, age at diagnosis, reasons for initial concern, and the specialists providing the diagnosis. In the 47,XXY cohort diagnosed postnatally, 59% presented with developmental delay, with a mean age at first parental concern of 5.2 years and mean age of diagnosis at 10.0 years. The remaining 41% presented with endocrinologic issues with a mean age at first concern of 19.1 years and mean age of diagnosis at 21.1 years. In the 48,XXYY group, 93% presented with developmental delay, with mean age at first parental concern of 2.4 years and mean age of diagnosis at 7.6 years. Hence, the average time from initial parental concern to diagnosis of 47,XXY or 48,XXYY ranges from 2 to 5 years, with those presenting with developmental issues having a longer lag to diagnosis compared to those presenting with endocrinologic issues. Increased awareness of the developmental, psychological, and medical features of 47,XXY and 48,XXYY is important to facilitate timely diagnosis and initiation of appropriate screenings and treatments that are important for optimal outcomes.
PMCID: PMC3558746  PMID: 23322622
Sex chromosomal aneuploidies; delayed diagnosis; medical support
21.  Atypical Presentations and Specific Genotypes are Associated with a Delay in Diagnosis in Females with Rett Syndrome 
There is often delay between onset of Rett syndrome symptoms and its diagnosis, possibly related to symptom presentation or socio-demographic factors. We hypothesized that girls with an atypical presentation or whose family had a lower socio-economic status would receive a later diagnosis. Female subjects with a confirmed diagnosis of Rett syndrome were sourced from the Australian Rett Syndrome and InterRett Databases. Variables analyzed included timing and development of symptoms; MECP2 mutation type; parental occupation and education; maternal age and birth-order. Residential location and socio-economic status were also analyzed for the Australian cases. Linear regression was used to determine relationships between these factors and age at diagnosis. A total of 909 cases were included. An older age of diagnosis was associated with later loss of hand function and speech, later onset of hand stereotypies and the presence of the p.R133C or p.R294X MECP2 mutation. Socio-economic factors did not predict age of diagnosis for Australian families. For families participating in the InterRett database, a younger age of diagnosis was associated with higher levels of parental education or occupation. A clinical picture consistent with the classic presentation of Rett syndrome is associated with an earlier diagnosis. Clinicians need to be alerted to the variable presentation of Rett syndrome including the milder phenotypes of cases with the p.R133C or p.R294X mutation. Educational resources to assist this understanding including guidance on when to request genetic testing could be useful to streamline the process of diagnosis in Rett syndrome.
PMCID: PMC3906205  PMID: 20815036
Rett syndrome; age at diagnosis; socio-economic status; symptom presentation; MECP2
22.  Search for Genetic Modifiers of IRF6 and Genotype-Phenotype Correlations in Van der Woude and Popliteal Pterygium Syndromes 
Van der Woude syndrome is the most common form of syndromic orofacial clefting, accounting for 1-2% of all patients with cleft lip and/or cleft palate. Van der Woude and popliteal pterygium syndromes are caused by mutations in IRF6, but phenotypic variability within and among families with either syndrome suggests that other genetic factors contribute to the phenotypes. The aim of this study was to identify common variants acting as genetic modifiers of IRF6 as well as genotype-phenotype correlations based on mutation type and location. We identified an association between mutations in the DNA-binding domain of IRF6 and limb defects (including pterygia). Although we did not detect formally significant associations with the genes tested, borderline associations suggest several genes that could modify the VWS phenotype, including FOXE1, TGFB3, and TFAP2A. Some of these genes are hypothesized to be part of the IRF6 gene regulatory network and may suggest additional genes for future study when larger sample sizes are also available. We also show that families with the Van der Woude phenotype but in whom no mutations have been identified have a lower frequency of cleft lip, suggesting there may be locus and/or mutation class differences in Van der Woude syndrome.
PMCID: PMC3898350  PMID: 23949966
Modifier gene; Van der Woude; popliteal pterygium; cleft; lip pit
23.  Thoracic Aortic Disease in Two Patients with Juvenile Polyposis Syndrome and SMAD4 mutations 
Dilation or aneurysm of the ascending aorta can progress to acute aortic dissection (Thoracic Aortic Aneurysms and Aortic Dissections, TAAD). Mutations in genes encoding TGF-β related proteins (TGFBR1, TGFBR2, FBN1, and SMAD3) cause syndromic and inherited TAAD. SMAD4 mutations are associated with juvenile polyposis (JPS) and a combined JPS-hereditary hemorrhagic telangiectasia (HHT) known as JPS-HHT. A family with JPS-HHT was reported to have aortic root dilation and mitral valve abnormalities. We report on two patients with JPS-HHT with SMAD4 mutations associated with thoracic aortic disease. The first patient, an 11-year-old boy without Marfan syndrome features, had JPS and an apparently de novo SMAD4 mutation (c.1340_1367dup28). Echocardiography showed mild dilation of the aortic annulus and aortic root, and mild dilation of the sinotubular junction and ascending aorta. Computed tomography confirmed aortic dilation and showed small pulmonary arteriovenous malformations (PAVM). The second patient, a 34-year-old woman with colonic polyposis, HHT, and Marfan syndrome, had a SMAD4 mutation (c.1245_1248delCAGA). Echocardiography showed mild aortic root dilation. She also had PAVM and hepatic focal nodular hyperplasia. Her family history was significant for polyposis, HHT, thoracic aortic aneurysm, and dissection and skeletal features of Marfan syndrome in her father. These two cases confirm the association of thoracic aortic disease with JPS-HHT resulting from SMAD4 mutations. We propose that the thoracic aorta should be screened in patients with SMAD4 mutations to prevent untimely death from dissection. This report also confirms that SMAD4 mutations predispose to TAAD.
PMCID: PMC3535513  PMID: 23239472
aortic dilation; hereditary hemorrhagic telangiectasia; juvenile polyposis Syndrome; SMAD4; TGF-beta signaling; thoracic aortic aneurysm and dissection
24.  Maternal Perspectives on the Return of Genetic Results: Context Matters 
The objectives of this study were to study maternal preferences for the return of their child’s genetic results and to describe the experiences, perceptions, attitudes and values that are brought to bear when individuals from different racial and cultural backgrounds consider participating in genetic research. We recruited women with diverse sociodemographic profiles to participate in seven focus groups. Twenty-eight percent of participants self-identified as Hispanic; 49% as White, Non-Hispanic; and 21% as Asian or Asian American. Focus groups were conducted in English or Spanish and were audio-recorded and transcribed verbatim. Transcripts were analyzed using qualitative thematic methods. Results indicated that preferences and decisions regarding the return of results may depend on both research and individual contextual factors. Participants understood the return of results as a complex issue, where individual and cultural differences in preferences are certain to arise. Another key finding was that participants desired an interpersonal, dynamic, flexible process that accommodated individual preferences and contextual differences for returning results. Our findings indicate a need to have well-developed systems for allowing participants to make and change over time their choices regarding the return of their child’s genetic results.
PMCID: PMC3535554  PMID: 23239553
genomic; genetic; research participation; return of results; context
25.  “Mandibulofacial Dysostosis with Microcephaly” Caused by EFTUD2 Mutations: Expanding the Phenotype 
Heterozygous mutations in the EFTUD2 were identified in 12 individuals with a rare sporadic craniofacial condition termed Mandibulofacial dysostosis with microcephaly (MIM 610536). We present clinical and radiographic features of three additional patients with de novo heterozygous mutations in EFTUD2.. Although clinical features overlap with findings of the original report (choanal atresia, cleft palate, maxillary and mandibular hypoplasia, and microtia), microcephaly was present in two of three patients and cognitive impairment was milder in those with head circumference proportional to height. Our cases expand the phenotypic spectrum to include epibulbar dermoids and zygomatic arch clefting. We suggest that craniofacial computed tomography studies to assess cleft of zygomatic arch may assist in making this diagnosis. We recommend consideration of EFTUD2 testing in individuals with features of oculo-auriculo-vertebral spectrum and bilateral microtia, or individuals with atypical CHARGE syndrome who do not have a CHD7 mutation, particularly those with a zygomatic arch cleft. The absence of microcephaly in one patient indicates that it is a highly variable phenotypic feature.
PMCID: PMC3535578  PMID: 23239648
craniofacial development; EFTUD2; epibulbar dermoid; craniofacial microsomia; oculo-auriculo-vertebral spectrum (OAVS); choanal atresia

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