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Angela E Lin

Publications and source records attributed to Angela E Lin.

At least 19 recordsLinked to original sources
PubMed2006

HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.

Costello syndrome is a rare condition comprising mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy, and/or atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities. Recently mutations in HRAS were identified in 12 Japanese and Italian patients with clinical information available on 7 of the Japanese patients. To expand the molecular delineation of Costello syndrome, we performed mutation analysis in 34 North American and 6 European (total 40) patients with Costello syndrome, and detected missense mutations in HRAS in 33 (82.5%) patients. All mutations affected either codon 12 or 13 of the protein product, with G12S occurring in 30 (90.9%) patients of the mutation-positive cases. In two patients, we found a mutation resulting in an alanine substitution in position 12 (G12A), and in one patient, we detected a novel mutation (G13C). Five different HRAS mutations have now been reported in Costello syndrome, however genotype-phenotype correlation remains incomplete.

Abnormalities, Multiple↗
PubMed2006

Clinician reviewers in birth defects surveillance programs: survey of the National Birth Defects Prevention Network.

BACKGROUND: Some birth defects surveillance programs utilize a clinician reviewer ("Clinician") to assist the multidisciplinary staff in the process of case review, coding and classification. The untested assumption is that expertise in the evaluation of individuals with birth defects and genetic syndromes in clinical practice, usually clinical genetics, is useful in reviewing medical records. METHODS: We conducted an exploratory survey of the 50 functioning birth defects surveillance programs that participated in the National Birth Defects Prevention Network in 2004. The survey was mailed electronically to program coordinators and included 10 questions with check-off option replies. Open-ended comments were also solicited. RESULTS: Responses were received from 31 of 50 (62%) programs, 21 (68%) which used a Clinician. In addition to the 9 centers that identified themselves as participants in the National Birth Defects Prevention Study (NBDPS), there were 12 non-NBDPS programs using a Clinician, 2 of whom were not clinical geneticists (1 nurse genetic counselor and 1 primary pediatrician). A total of 86% (18/21) of Clinicians were employed part-time or as consultants; 1 was full-time, and 2 were volunteers. In addition to the core activities of classifying defects and reviewing cases to determine if a syndrome was present, over one-half of the Clinicians participated in education of birth defects surveillance programs staff, research, and program development. Most (86%; 18/21) Clinicians had been trained informally for their roles. Only 1 had received a formal performance review. CONCLUSIONS: Aside from the 9 centers in the NBDPS in which the position of Clinician is funded by the Centers for Disease Control and Prevention (CDC), about one-half of the remaining respondent birth defects surveillance programs used a Clinician. Future research is needed to determine why a birth defects surveillance program hires or refrains from using a Clinician, and whether a Clinician accomplishes the desired goals. This survey reveals a lack of formal training for the Clinicians in their roles in the surveillance programs, and a lack of quality monitors, which might be addressed in the future.

Congenital Abnormalities↗
PubMed2006

Writing for scientific publication: tips for getting started.

Pediatricians in training and clinical practice may be eager to submit their first scientific publication by writing a letter to the editor, case report, review article, or short clinical series. Unfortunately, the would-be author encounters a literary developmental delay when facing the blank page or computer screen. This article is dedicated to the novice author and offers practical tips on writing the first manuscript. Authors are encouraged to draw from their extensive experience writing other materials and to approach the task in a systematic way. Computer technology and software developments should facilitate the process.

Computers↗
PubMed2005

Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation.

CHARGE syndrome is a well-established multiple-malformation syndrome with distinctive consensus diagnostic criteria. Characteristic associated anomalies include ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogenital anomalies, and growth retardation. Recently, mutations of the chromodomain helicase DNA-binding protein gene CHD7 were reported to be a major cause of CHARGE syndrome. We sequenced the CHD7 gene in 110 individuals who had received the clinical diagnosis of CHARGE syndrome, and we detected mutations in 64 (58%). Mutations were distributed throughout the coding exons and conserved splice sites of CHD7. Of the 64 mutations, 47 (73%) predicted premature truncation of the protein. These included nonsense and frameshift mutations, which most likely lead to haploinsufficiency. Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations (54 of 59 in the mutation-positive group vs. 30 of 42 in the mutation-negative group; P=.014), coloboma of the eye (55 of 62 in the mutation-positive group vs. 30 of 43 in the mutation-negative group; P=.022), and facial asymmetry, often caused by seventh cranial nerve abnormalities (36 of 56 in the mutation-positive group vs. 13 of 39 in the mutation-negative group; P=.004). Mouse embryo whole-mount and section in situ hybridization showed the expression of Chd7 in the outflow tract of the heart, optic vesicle, facio-acoustic preganglion complex, brain, olfactory pit, and mandibular component of the first branchial arch. Microarray gene-expression analysis showed a signature pattern of gene-expression differences that distinguished the individuals with CHARGE syndrome with CHD7 mutation from the controls. We conclude that cardiovascular malformations, coloboma, and facial asymmetry are common findings in CHARGE syndrome caused by CHD7 mutation.

Abnormalities, Multiple↗
PubMed2005

Cardiovascular malformations in Fryns syndrome: is there a pathogenic role for neural crest cells?

We performed a comprehensive literature and case report review to characterize the cardiovascular malformations (CVMs) associated with Fryns syndrome (OMIM #229850), a multiple congenital anomaly/mental retardation syndrome consisting of diaphragmatic defects, significant pulmonary hypoplasia, distinctive facial appearance, distal digital hypoplasia, and numerous other external and internal anomalies. A total of 112 patients meeting diagnostic guidelines for Fryns syndrome were identified, of whom 82 met narrowly defined criteria (Group I) and 30 met broader diagnostic criteria (Group II). Twelve patients reported as having Fryns syndrome with atypical features (Group III) were also analyzed. A CVM was reported in 51% (42 of 82) of Group I patients, most commonly an atrial or ventricular septal defect (VSD) (23 of 42, 55%). Conotruncal and aortic arch CVMs were common (11 of 42, 26%), but not significantly so compared to the general population of infants to age 1 year [Ferencz et al., 1997]. Recognizing that minor septal defects associated with congenital diaphragmatic hernia (CDH) may occur in response to altered hemodynamics (instead of being a bonafide CVM), we excluded four patients reported as having hemodynamically insignificant VSDs. Following these exclusions, conotruncal CVMs were found more commonly than in the general population (11 of 38, 29%, P < or = 0.025). In Group II, 9 of 30 (30%) had a CVM with no predominant type among the small number of cases reviewed. Among the atypical Fryns syndrome patients in Group III, half (6 of 12, 50%) had a CVM; most (4 of 6, 67%) were conotruncal, in particular, type B interrupted aortic arch (3 of 4). Patients with Fryns syndrome have a high rate of CVMs, warranting thorough cardiac evaluation including echocardiogram (fetal and/or postnatal) in all patients, similar to the evaluation for other patients with diaphragmatic hernia. The possible association between conotruncal CVMs and Fryns syndrome may provide additional support for an etiologic role of genes related to neural crest cell development in the pathogenesis of Fryns syndrome and hence, congenital diaphragmatic hernia.

Abnormalities, Multiple↗
PubMed2005

Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.

Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.

Abnormalities, Multiple↗
PubMed2005

Myocardial storage of chondroitin sulfate-containing moieties in Costello syndrome patients with severe hypertrophic cardiomyopathy.

Costello syndrome is a distinctive multiple congenital anomaly syndrome, characterized by loose soft skin with deep palmar and plantar creases, loose joints, distinctive coarse facial features, skeletal abnormalities, cardiac abnormalities (cardiovascular malformation (CVM), hypertrophic cardiomyopathy, tachycardia), predisposition to malignancy, developmental delays, and mental retardation. Previous studies with cultured fibroblasts from individuals with Costello syndrome demonstrate excessive accumulation of chondroitin sulfate-bearing proteoglycans, associated with both impaired formation of elastic fibers and an unusually high rate of cellular proliferation. Despite multiple clinical reports of cardiac abnormalities, there has been only one previously published report describing post-mortem findings in hearts from Costello syndrome patients. Here we provide a detailed description of the post-mortem findings of the hearts of three children with Costello syndrome. Routine histological examination and results of targeted histochemical and immunohistochemical studies revealed that in addition to cardiomyocyte hypertrophy, these hearts also demonstrated massive pericellular and intracellular accumulation of chondroitin sulfate-bearing proteoglycans and a marked reduction of elastic fibers. Normal stroma was replaced by multifocal collagenous fibrosis. Most peculiar was the finding that the bulk of the chondroitin sulfate accumulated in these Costello syndrome hearts is a chondroitin-6-sulfate. In contrast, deposition of chondroitin-4 sulfate was below the level detected in normal hearts. We propose that an imbalance in sulfation of chondroitin sulfate molecules and subsequent accumulation of chondroitin-6-sulfate in cardiomyocytes contribute to the development of the hypertrophic cardiomyopathy of Costello syndrome.

Abnormalities, Multiple↗
PubMed2005

Further delineation of Kabuki syndrome in 48 well-defined new individuals.

Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases-providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined.

Abnormalities, Multiple↗
PubMed2005

Fryns syndrome with Hirschsprung disease: support for possible neural crest involvement.

Fryns syndrome is an autosomal recessive multiple congenital anomaly/mental retardation syndrome characterized by coarse face, distal limb hypoplasia, and diaphragmatic anomalies. We describe a newborn girl with Fryns syndrome and Hirschsprung disease, an association that has been reported in five previous cases. These patients support the hypothesis that the neural crest plays a role in the pathogenesis of Fryns syndrome. Clinically asymptomatic or subtle anomalies that are in the spectrum of neural crest maldevelopment should be sought in all patients with Fryns syndrome including stillbirths, neonatal deaths, as well as long-term survivors. We suspect that the clinical observation about Hirschsprung disease and Fryns syndrome may provide insight into its molecular mechanisms and candidate genes.

Abnormalities, Multiple↗
PubMed2004

Clonazepam use in pregnancy and the risk of malformations.

BACKGROUND: Clonazepam (Klonopin) is a benzodiazepine that has been used widely to treat seizures and conditions such as panic attacks and anxiety disorder. However, the current findings about its use in pregnancy are derived from limited studies of small sample size. Because it is commonly prescribed during pregnancy, more information about its safety is needed. METHODS: The medical records of 28,565 infants were surveyed as part of a hospital-based malformation surveillance program to identify those who had been exposed prenatally to an anticonvulsant, including clonazepam. RESULTS: During a 32-month period, 166 anticonvulsant-exposed infants were identified; 52 had been exposed to clonazepam, 43 as monotherapy. A total of 33 (76.7%) of the monotherapy infants were exposed during the first trimester. One (3.0%) infant had dysmorphic features, growth retardation, and a heart malformation (tetralogy of Fallot). CONCLUSIONS: This study did not observe an increase in major malformations in births exposed to clonazepam monotherapy. However, this study is not large enough to have adequate power to determine whether or not the rate of major malformations is increased in clonazepam-exposed pregnancies. No increase has been identified in three other case series. Although the number of patients in this series was larger than previous reports, continued monitoring of pregnancies is needed to determine whether or not clonazepam is teratogenic.

Abnormalities, Drug-Induced↗
PubMed2003

A new X-linked syndrome with agenesis of the corpus callosum, mental retardation, coloboma, micrognathia, and a mutation in the Alpha 4 gene at Xq13.

We describe two brothers with a unique pattern of malformations that includes coloboma (iris, optic nerve), high forehead, severe retrognathia, mental retardation, and agenesis of the corpus callosum (ACC). Both boys have low-set cupped ears with sensorineural hearing loss, normal phallus, pectus excavatum, scoliosis, and short stature. One brother had choanal atresia and cardiac defects consisting of ventricular septal defect (VSD) and patent ductus arteriosus (PDA) which resolved spontaneously. Differential diagnosis between a number of clinical entities was considered, however, because ACC and the distinctive facial features were reminiscent of FG syndrome, DNA was analyzed for markers linked to the FGS1 locus at Xq13-q21. Notably, the brothers were concordant for markers spanning this presumed FG region, and in both we have identified adjacent alterations (-57delT and T-55A) in the Alpha 4 gene located within this interval. Alpha 4 is a regulatory subunit of the major cellular phosphatase, PP2A, that has recently been shown to interact with MID1, the product of the gene mutated in X-linked Opitz GBBB syndrome. The double nucleotide change identified in this family was not observed in 410 control chromosomes, suggesting that it may be a pathogenetic change. Altered expression of Alpha 4, through either a change in translational efficiency, mRNA stability or splicing, could explain the clinical phenotype in these boys and the phenotypic overlap with Opitz GBBB syndrome.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Toward a genetic etiology of CHARGE syndrome: I. A systematic scan for submicroscopic deletions.

CHARGE syndrome is a distinctive subgroup within the more heterogeneous group of patients with CHARGE association. While significant progress has been made in the clinical delineation of this syndrome, the molecular basis of the disorder remains unknown. Based on the complex phenotype, some overlap with DiGeorge/velocardiofacial syndrome (DGS/VCFS), and its estimated population incidence, we hypothesized that CHARGE syndrome could be caused by an unidentified genomic microdeletion. In order to address this hypothesis, we carried out a genome-wide screen for loss of expected heterozygosity using 811 microsatellite markers in ten CHARGE syndrome subjects and their unaffected parents. Eight markers gave results suggestive of failure to inherit one parental allele. These loci were tested with fluorescence in situ hybridization (FISH), but none showed evidence of deletion. This screen sets upper limits on the length of a CHARGE-related microdeletion, should that be the genetic mechanism underlying the phenotype.

Alleles↗
PubMed2003

Guidelines for case classification for the National Birth Defects Prevention Study.

BACKGROUND: Previous studies have suggested that etiologic heterogeneity may complicate epidemiologic analyses designed to identify risk factors for birth defects. Case classification uses knowledge of embryologic and pathogenetic mechanisms to make case groups more homogeneous and is important to the success of birth defects studies. METHODS: The goal of the National Birth Defects Prevention Study (NBDPS), an ongoing multi-site case-control study, is to identify environmental and genetic risk factors for birth defects. Information on environmental risk factors is collected through an hour-long maternal interview, and DNA is collected from the infant and both parents for evaluation of genetic risk factors. Clinical data on infants are reviewed by clinical geneticists to ensure they meet the detailed case definitions developed specifically for the study. To standardize the methods of case classification for the study, an algorithm has been developed to guide NBDPS clinical geneticists in this process. RESULTS: Methods for case classification into isolated, multiple, and syndrome categories are described. Defects considered minor for the purposes of case classification are defined. Differences in the approach to case classification for studies of specific defects and of specific exposures are noted. CONCLUSIONS: The case classification schema developed for the NBDPS may be of value to other clinicians working on epidemiologic studies of birth defects etiology. Consideration of these guidelines will lead to more comparable case groups, an important element of careful studies aimed at identifying risk factors for birth defects.

Adult↗
PubMed2002

Further delineation of cardiac abnormalities in Costello syndrome.

We review the cardiac abnormalities in 94 patients (27 new, 67 literature) with Costello syndrome, an increasingly recognized syndrome consisting of increased birth weight, postnatal growth retardation, and distinctive facial, skin, and musculoskeletal features (MIM 218040). A cardiac abnormality was found in 59 (63%) patients, with each of three categories occurring in approximately one-third of patients. A cardiovascular malformation (CVM) was noted in 30%, typically pulmonic stenosis (46% of those with a CVM). Cardiac hypertrophy was reported in 34%, which involved the left ventricle in 50% and was usually consistent with classic hypertrophic cardiomyopathy (HCM). A variety of rhythm disturbances were reported in 33%. Most (74%) were atrial tachycardia that was reported as supraventricular, chaotic, multifocal, or ectopic. Of 31 patients with a rhythm abnormality, 22 (68%) had an additional abnormality, i.e., CVM (4), cardiac hypertrophy (12), or both (6). Nine patients had isolated dysrhythmia, five (56%) of whom died. All of the 12 (13%) patients who died had a cardiac abnormality. One patient died of embryonal rhabdomyosarcoma, but in the remainder, a cardiac cause of death could not be disproved. All patients with Costello syndrome need a baseline cardiology evaluation with echocardiography and Holter monitoring. Additional prospective evaluations, even in patients without apparent cardiac abnormalities, would be prudent, although data are insufficient to propose a specific schedule.

Abnormalities, Multiple↗