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Featured researches published by Linda Nicholson.


American Journal of Medical Genetics Part A | 2006

HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation

Karen W. Gripp; Angela E. Lin; Deborah L. Stabley; Linda Nicholson; Charles I. Scott; Daniel Doyle; Yoko Aoki; Yoichi Matsubara; Elaine H. Zackai; Pablo Lapunzina; Antonio González-Meneses; Jennifer Holbrook; Cynthia A. Agresta; Iris L. Gonzalez; Katia Sol-Church

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.


American Journal of Medical Genetics Part A | 2007

Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome†‡§

Karen W. Gripp; Angela E. Lin; Linda Nicholson; William Allen; Andrea Cramer; Kenneth Lyons Jones; Wendy Kutz; Dawn Peck; Michael A. Rebolledo; Patricia G. Wheeler; William G. Wilson; Mohamad M. Al-Rahawan; Deborah L. Stabley; Katia Sol-Church

Because Cardio‐facio‐cutaneous (CFC) syndrome has significant phenotypic overlap with Costello syndrome, it may be difficult to establish the diagnosis on a clinical basis. The recent discoveries of germline HRAS mutations in patients with Costello syndrome and mutations in BRAF, MEK1, and MEK2 in CFC syndrome uncovered the biologic mechanism for the shared phenotypic findings based on the close interaction of the affected gene products within the MAP kinase pathway. We evaluated a series of patients who were either clinically diagnosed with Costello syndrome, or in whom the diagnoses of both Costello and CFC syndromes were considered. After excluding mutations in HRAS, we identified eight changes in BRAF and five in MEK1. Five mutations are novel, and all changes occurred de novo among those triads tested. A review of the clinical abnormalities showed important differences between patients with either a BRAF or MEK1 mutation, and those previously reported with an HRAS mutation. Statistical significance was achieved, despite the relatively small number of patients with BRAF and MEK1 mutations reported here, for polyhydramnios, growth hormone deficiency and the presence of more than one papilloma, which were less common in CFC compared to HRAS mutation positive patients. Although both CFC and Costello syndrome are characterized by cardiac abnormalities in about three‐fourths of patients, the pattern of congenital heart defects (CHD), hypertrophic cardiomyopathy (HCM), and tachycardia differs somewhat. CHD, especially pulmonic stenosis associated with a secundum‐type atrial septal defect, are more common in CFC than Costello syndrome (P = 0.02). Atrial tachycardia is less frequent in CFC patients with BRAF or MEK1 mutations, compared to Costello syndrome patients with HRAS mutation (P = 0.04). Chaotic atrial rhythm or multifocal atrial tachycardia was observed only in Costello syndrome. Malignant tumors have been viewed as characteristic for Costello syndrome due to HRAS mutations, however, we report here on a MEK1 mutation in a patient with a malignant tumor, a hepatoblastoma. Although this indicates that the presence of a tumor is not specific for Costello syndrome with HRAS mutation, it is noteworthy that the tumor histology differs from those commonly seen in Costello syndrome. Based on these clinical differences we suggest that patients with BRAF and MEK mutations should be diagnosed with CFC syndrome, and the diagnosis of Costello syndrome be reserved for patients with HRAS mutations.


American Journal of Medical Genetics Part A | 2006

Somatic mosaicism for an HRAS mutation causes Costello syndrome

Karen W. Gripp; Deborah L. Stabley; Linda Nicholson; Jodi D. Hoffman; Katia Sol-Church

De novo heterozygous HRAS point mutations have been reported in more than 81 patients with Costello syndrome (CS), but genotype/phenotype correlation remains incomplete because the majority of patients share a common mutation, G12S, seen in 65/81 (80%). Somatic HRAS mutations have previously been identified in solid tumors, and mutation hot spots related to a gain‐of‐function effect of the gene product are known. The germline mutations causing CS occur at these hot spots and convey a gain‐of‐function effect, thus accounting for the greatly increased cancer risk. Diagnostic testing for HRAS mutations is now available and the identification of a mutation in a patient with consistent clinical findings confirms a diagnosis of CS. It is not clear yet if the absence of an HRAS mutation precludes a diagnosis of CS. Because there is a significant overlap in the clinical findings of Costello, cardio‐facio‐cutaneous, and Noonan syndromes, diagnostic uncertainty remains in patients lacking an HRAS mutation. We report here on a female with findings suggestive of CS in whom mutation analysis performed with standard techniques on white blood cell derived DNA did not show an HRAS mutation. However, analysis of DNA derived from three independently collected buccal swabs showed a sequence change qualitatively consistent with the G12S mutation. Allelic quantitation showed the presence of the mutation in ∼25%–30% of the sampled buccal cells. In this patient, standard technology failed to identify the disease causing mutation on DNA derived from a blood sample, highlighting the potential pitfalls in the interpretation of negative mutation studies. This is the first reported CS patient mosaic for the common HRAS mutation, likely due to a somatic mutation occurring very early in fetal development.


American Journal of Medical Genetics Part A | 2006

Frontometaphyseal dysplasia: mutations in FLNA and phenotypic diversity.

Stephen P. Robertson; Zandra A. Jenkins; Timothy R. Morgan; Lesley C. Adès; Salim Aftimos; Odile Boute; Torunn Fiskerstrand; Sixto García-Miñaúr; Arthur W. Grix; Andrew Green; Vazken M. Der Kaloustian; Ray Lewkonia; Brenda McInnes; Mieke M. van Haelst; Grazia Macini; Tamás Illés; Geert Mortier; Ruth Newbury-Ecob; Linda Nicholson; Charles I. Scott; Karolina Ochman; Izabela Brozek; Deborah J. Shears; Andrea Superti-Furga; Mohnish Suri; Margo Whiteford; Andrew O.M. Wilkie; Deborah Krakow

Frontometaphyseal dysplasia is an X‐linked trait primarily characterized by a skeletal dysplasia comprising hyperostosis of the skull and modeling anomalies of the tubular bones. Extraskeletal features include tracheobronchial, cardiac, and urological malformations. A proportion of individuals have missense mutations or small deletions in the X‐linked gene, FLNA. We report here our experience with comprehensive screening of the FLNA gene in a group of 23 unrelated probands (11 familial instances, 12 simplex cases; total affected individuals 32) with FMD. We found missense mutations leading to substitutions in the actin‐binding domain and within filamin repeats 9, 10, 14, 16, 22, and 23 of filamin A in 13/23 (57%) of individuals in this cohort. Some mutations present with a male phenotype that is characterized by a severe skeletal dysplasia, cardiac, and genitourinary malformations that leads to perinatal death. Although no phenotypic feature consistently discriminates between females with FMD who are heterozygous for FLNA mutations and those in whom no FLNA mutation can be identified, there is a difference in the degree of skewing of X‐inactivation between these two groups. This observation suggests that locus heterogeneity may exist for this disorder.


American Journal of Medical Genetics Part A | 2008

Costello syndrome associated with novel germline HRAS mutations: An attenuated phenotype?

Karen W. Gripp; A. Micheil Innes; Marni E. Axelrad; Tanya L. Gillan; Jillian S. Parboosingh; Christine Davies; Norma J. Leonard; Monique Lapointe; Daniel Doyle; Sarah Catalano; Linda Nicholson; Deborah L. Stabley; Katia Sol-Church

Costello syndrome is a rare congenital disorder typically characterized by severe failure‐to‐thrive, cardiac abnormalities including tachyarrhythmia and hypertrophic cardiomyopathy, distinctive facial features, a predisposition to papillomata and malignant tumors, neurologic abnormalities, developmental delay, and mental retardation. Its underlying cause is de novo germline mutations in the oncogene HRAS. Almost all Costello syndrome mutations affect one of the glycine residues in position 12 or 13 of the protein product. More than 80% of patients with Costello syndrome share the same underlying mutation, resulting in a G12S amino acid change. We report on two patients with novel HRAS mutations affecting amino acids 58 (T58I) and 146 (A146V), respectively. Despite facial features that appear less coarse than those typically seen in Costello patients, both patients show many of the physical and developmental problems characteristic for Costello syndrome. These novel HRAS mutations may be less common than the frequently reported G12S change, or patients with these changes may be undiagnosed due to their less coarse facial features. In addition to the findings previously known to occur in Costello syndrome, one of our patients had hypertrophic pyloric stenosis. This led us to review the medical histories on a cohort of proven HRAS mutation positive Costello syndrome patients, and we found a statistically significantly (P < 0.001) increased frequency of pyloric stenosis in Costello syndrome (5/58) compared to the general population frequency of 2–3/1,000. Thus we add hypertrophic pyloric stenosis to the abnormalities seen with increased frequency in Costello syndrome.


American Journal of Medical Genetics Part A | 2004

Subtelomeric deletions of chromosome 9q: A novel microdeletion syndrome

Douglas R. Stewart; Alina Huang; Francesca Faravelli; Britt-Marie Anderlid; Livija Medne; Karen L. Ciprero; Maninder Kaur; Elena Rossi; Romano Tenconi; Magnus Nordenskjöld; Karen W. Gripp; Linda Nicholson; Wendy S. Meschino; Esther Capua; Oliver Quarrell; Jonathon Flint; Mira Irons; Philip F. Giampietro; David B. Schowalter; Christina Zaleski; M. Malacarne; Elaine H. Zackai; Nancy B. Spinner; Ian D. Krantz

Fluorescent in situ hybridization (FISH) screening of subtelomeric rearrangements has resulted in the identification of previously unrecognized chromosomal causes of mental retardation with and without dysmorphic features. This article reports the phenotypic and molecular breakpoint characterization in a cohort of 12 patients with subtelomeric deletions of chromosome 9q34. The phenotypic findings are consistent amongst these individuals and consist of mental retardation, distinct facial features and congenital heart defects (primarily conotruncal defects). Detailed breakpoint mapping by FISH, microsatellite and single nucleotide polymorphism (SNP) genotyping analysis has narrowed the commonly deleted region to an approximately 1.2 Mb interval containing 14 known transcripts. The majority of the proximal deletion breakpoints fall within a 400 kb interval between SNP markers C12020842 proximally and C80658 distally suggesting a common breakpoint in this interval.


American Journal of Medical Genetics Part A | 2009

Male-to-male transmission of Costello syndrome: G12S HRAS germline mutation inherited from a father with somatic mosaicism†‡

Katia Sol-Church; Deborah L. Stabley; Laurie A. Demmer; Abigail Agbulos; Angela E. Lin; Leslie B. Smoot; Linda Nicholson; Karen W. Gripp

Costello syndrome is a rare congenital anomaly syndrome associated with mental retardation and predisposition to benign and malignant tumors, caused by heterozygous missense mutations in the HRAS oncogene. Previously, all molecularly analyzed mutations appeared de novo, and most arose in the paternal germline. A single patient with somatic mosaicism for a Costello syndrome causing HRAS mutation has been reported. Here we describe the first documented transmission of an HRAS mutation from a parent with somatic mosaicism to a child with typical Costello syndrome. Prior to the identification of the underlying gene mutation in Costello syndrome, this family had been identified clinically. The proband was subsequently found to carry a G12S HRAS germline mutation. Testing of the parents for parental origin identified his father as mosaic for the same HRAS mutation. The mother was found not to carry an HRAS mutation. The causative familial mutation is identified as a c.34G > A, which is the most common mutation in the HRAS gene in patients with Costello syndrome. The father carries the mutation in 7–8% of his alleles. This is the second case of mosaicism observed in Costello syndrome and the first direct molecular evidence of father‐to‐son transmission of the disease‐causing mutation. Our observation underlines the importance of parental evaluation, and may have implications for genetic counseling and clinical practice.


American Journal of Medical Genetics Part A | 2007

Longitudinal assessment of cognitive characteristics in Costello syndrome

Marni E. Axelrad; Linda Nicholson; Deborah L. Stabley; Katia Sol-Church; Karen W. Gripp

Costello syndrome encompasses pre‐ and postnatal medical problems including polyhydramnios, failure to thrive, cardiac complications, and an increased risk for solid tumors. Hypotonia and developmental delay are typical in infancy, and mental retardation can be diagnosed in older patients. Previous studies on the cognitive development in Costello syndrome relied on clinically diagnosed cases. The recent discovery of heterozygous HRAS mutations allows for molecular confirmation of the clinical diagnoses. We report here on cognitive abilities and adaptive behavior in the first cohort of patients with molecularly confirmed diagnoses. Further, this is the first longitudinal assessment of cognitive function in this patient population. Sixteen patients with identified HRAS mutations were tested, and 14 completed the Leiter International Performance Scale—Revised. The mean Full‐Scale IQ score of 57 (range 30–87) was within the range of mild Mental Retardation. Analysis of test component subsets showed a relative strength in Fluid Reasoning with a mean score of 69 (range 48–98), in the mild range of Mental Retardation. Longitudinal analysis was performed for 12 patients by comparison of data obtained at the first evaluation (T1) to results obtained 2 years later (T2). In these patients intellectual and language abilities remained stable, and no deterioration was seen. We have thus shown that Costello syndrome is a static condition regarding intellectual and language abilities. The Leiter‐R Memory Screen indicated functioning in the mildly delayed range for the majority of patients. Adaptive behavior was evaluated using the Vineland tool, and longitudinal data comparison for adaptive behavior showed improvements in Daily Living Skills, Communication, and the Adaptive Behavior Composite. However, these results must be interpreted cautiously as the measuring tool was updated from T1 to T2. Receptive language skills were measured with the Peabody Picture Vocabulary Test‐III, showing a mean receptive vocabulary standard score of 65 (SD 15) in the Extremely Low range. Expressive language skills, as measured by the Expressive Vocabulary Test (EVT), scored a mean of 51 (SD 14), in the Extremely Low range. However, half of the subjects obtained the lowest possible score on the EVT, demonstrating that this is not the ideal tool for use in this patient population.


American Journal of Medical Genetics Part A | 2004

Adaptive skills, cognitive, and behavioral characteristics of Costello syndrome.

Marni E. Axelrad; Rochelle Glidden; Linda Nicholson; Karen W. Gripp

Costello syndrome is a rare congenital disorder whose diagnosis is based on clinical findings. The underlying genetic cause has not been identified. Common characteristics include failure to thrive, feeding problems, short stature, coarsening of facial features, developmental delay, mental retardation, skeletal problems, cardiac complications, and increased risk for solid tumors. Given its rarity, existing literature is limited regarding its natural course. Developmental milestones and intellectual functioning have never been systematically studied in this population, therefore this study focused on defining developmental and intellectual attributes. Data was obtained through solicited participation at the 3rd International Costello Syndrome Meeting. A total of 18 children (age 3–20 years) were administered the Leiter‐R brief‐IQ and the Peabody picture vocabulary test (PPVT)‐III to assess nonverbal cognitive functioning and receptive vocabulary. Parents/guardians completed the child behavior checklist (CBCL) and participated in an interview process to complete the survey form of the Vineland adaptive behavior scales to assess emotional/behavioral issues and adaptive behavior. Results indicated that nonverbal cognitive functioning ranged from 1.5 to 4.3 SD below the age mean. Receptive vocabulary skills ranged from average functioning to 4 SD below the age mean. Adaptive behavior composites were all in the low range (2.0 to >5.0 SD below age mean), however there was significant variability in the range of domain scores. CBCL results ranged from normal to clinically significant across various clinical parameters. These data support a generalized descriptive pattern of developmental delay and mental retardation, with noted variability in receptive language, level of adaptive behavior functioning, and emotional/behavioral aspects. Skills and behavior are compared to existing literature of children with various syndromes.


Human Genetics | 2005

Observation of a parental inversion variant in a rare Williams–Beuren syndrome family with two affected children

Stephen W. Scherer; Karen W. Gripp; Jaume Lucena; Linda Nicholson; Jean-Paul Bonnefont; Luis A. Pérez-Jurado; Lucy R. Osborne

The Williams–Beuren syndrome (WBS) region at 7q11.23 is subject to several genomic rearrangements, one of which, the WBSinv-1 variant, is an inversion polymorphism. The WBSinv-1 chromosome has been shown to occur frequently in parents of individuals with WBS, implying that it predisposes the region to the WBS deletion. Here we investigate two WBS families with multiple affected children, and show that in one family, both siblings have a deletion on a WBSinv-1 chromosome background that arose due to interchromosomal recombination. These results suggest that the two WBS deletions in this family were independent events, and that there is likely a significant increase in the risk of deletion of the WBS region associated with the WBSinv-1 chromosome. The rarity of multiplex WBS families would suggest that the overall risk of having a child with WBS is still relatively low; however, families with an existing member with WBS may choose to opt for WBSinv-1 testing and genetic counseling.

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Karen W. Gripp

Children's Hospital of Philadelphia

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Charles I. Scott

Alfred I. duPont Hospital for Children

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Deborah L. Stabley

Alfred I. duPont Hospital for Children

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Katia Sol-Church

Alfred I. duPont Hospital for Children

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Elaine H. Zackai

Children's Hospital of Philadelphia

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Torunn Fiskerstrand

Haukeland University Hospital

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