Publications by authors named "Peter J Ainsworth"

17 Publications

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Genetic and epigenetic profiling of BRCA1/2 in ovarian tumors reveals additive diagnostic yield and evidence of a genomic BRCA1/2 DNA methylation signature.

J Hum Genet 2020 Oct 1;65(10):865-873. Epub 2020 Jun 1.

Molecular Diagnostics Division, Molecular Genetics Laboratory, London Health Sciences Centre, London, ON, Canada.

Poly-ADP-ribose-polymerase inhibitor (PARPi) treatment is indicated for advanced-stage ovarian tumors with BRCA1/2 deficiency. The "BRCAness" status is thought to be attributed to a tumor phenotype associated with a specific epigenomic DNA methylation profile. Here, we examined the diagnostic impact of combined BRCA1/2 sequence, copy number, and promoter DNA methylation analysis, and evaluated whether genomic DNA methylation patterns can predict the BRCAness in ovarian tumors. DNA sequencing of 172 human tissue samples of advanced-stage ovarian adenocarcinoma identified 36 samples with a clinically significant tier 1/2 sequence variants (point mutations and in/dels) and 9 samples with a CNV causing a loss of function in BRCA1/2. DNA methylation analysis of the promoter of BRCA1/2 identified promoter hypermethylation of BRCA1 in two mutation-negative samples. Computational modeling of genome-wide methylation markers, measured using Infinium EPIC arrays, resulted in a total accuracy of 0.75, sensitivity: 0.83, specificity: 0.64, positive predictive value: 0.76, negative predictive value: 0.74, and area under the receiver's operating curve (AUC): 0.77, in classifying tumors harboring a BRCA1/2 defect from the rest. These findings indicate that the assessment of CNV and promoter DNA methylation in BRCA1/2 increases the cumulative diagnostic yield by 10%, compared with the 20% yield achieved by sequence variant analysis alone. Genomic DNA methylation data can partially predict BRCAness in ovarian tumors; however, further investigation in expanded BRCA1/2 cohorts is needed, and the effect of other double strand DNA repair gene defects in these tumors warrants further investigations.
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http://dx.doi.org/10.1038/s10038-020-0780-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449880PMC
October 2020

Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.

Am J Hum Genet 2020 03 27;106(3):356-370. Epub 2020 Feb 27.

Université de Paris, Epigénétique et Destin Cellulaire, CNRS, 75013 Paris, France.

Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.
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http://dx.doi.org/10.1016/j.ajhg.2020.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058829PMC
March 2020

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions.

Am J Hum Genet 2019 04 28;104(4):685-700. Epub 2019 Mar 28.

Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A 5W9, Canada. Electronic address:

Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained. Some of these cases have been shown to result from DNA methylation defects at a single locus (epi-variants), while others can exhibit syndrome-specific DNA methylation changes across multiple loci (epi-signatures). Here, we investigate the clinical diagnostic utility of genome-wide DNA methylation analysis of peripheral blood in unresolved ND/CAs. We generate a computational model enabling concurrent detection of 14 syndromes using DNA methylation data with full accuracy. We demonstrate the ability of this model in resolving 67 individuals with uncertain clinical diagnoses, some of whom had variants of unknown clinical significance (VUS) in the related genes. We show that the provisional diagnoses can be ruled out in many of the case subjects, some of whom are shown by our model to have other diseases initially not considered. By applying this model to a cohort of 965 ND/CA-affected subjects without a previous diagnostic assumption and a separate assessment of rare epi-variants in this cohort, we identify 15 case subjects with syndromic Mendelian disorders, 12 case subjects with imprinting and trinucleotide repeat expansion disorders, as well as 106 case subjects with rare epi-variants, a portion of which involved genes clinically or functionally linked to the subjects' phenotypes. This study demonstrates that genomic DNA methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases and highlights the potential value of epigenomic testing in the routine clinical assessment of ND/CAs.
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http://dx.doi.org/10.1016/j.ajhg.2019.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451739PMC
April 2019

BAFopathies' DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes.

Nat Commun 2018 11 20;9(1):4885. Epub 2018 Nov 20.

Department of Pathology and Laboratory Medicine, Western University, London, N6A 5W9, ON, Canada.

Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across a wide range of neurodevelopmental conditions including other chromatin remodeling and epigenetic machinery disorders. We demonstrate that a machine-learning model trained on this DNA methylation profile can resolve ambiguous clinical cases, reclassify those with variants of unknown significance, and identify previously undiagnosed subjects through targeted population screening.
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http://dx.doi.org/10.1038/s41467-018-07193-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244416PMC
November 2018

Clinical Validation of Copy Number Variant Detection from Targeted Next-Generation Sequencing Panels.

J Mol Diagn 2017 11 15;19(6):905-920. Epub 2017 Aug 15.

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada. Electronic address:

Next-generation sequencing (NGS) technology has rapidly replaced Sanger sequencing in the assessment of sequence variations in clinical genetics laboratories. One major limitation of current NGS approaches is the ability to detect copy number variations (CNVs) approximately >50 bp. Because these represent a major mutational burden in many genetic disorders, parallel CNV assessment using alternate supplemental methods, along with the NGS analysis, is normally required, resulting in increased labor, costs, and turnaround times. The objective of this study was to clinically validate a novel CNV detection algorithm using targeted clinical NGS gene panel data. We have applied this approach in a retrospective cohort of 391 samples and a prospective cohort of 2375 samples and found a 100% sensitivity (95% CI, 89%-100%) for 37 unique events and a high degree of specificity to detect CNVs across nine distinct targeted NGS gene panels. This NGS CNV pipeline enables stand-alone first-tier assessment for CNV and sequence variants in a clinical laboratory setting, dispensing with the need for parallel CNV analysis using classic techniques, such as microarray, long-range PCR, or multiplex ligation-dependent probe amplification. This NGS CNV pipeline can also be applied to the assessment of complex genomic regions, including pseudogenic DNA sequences, such as the PMS2CL gene, and to mitochondrial genome heteroplasmy detection.
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http://dx.doi.org/10.1016/j.jmoldx.2017.07.004DOI Listing
November 2017

Identification of epigenetic signature associated with alpha thalassemia/mental retardation X-linked syndrome.

Epigenetics Chromatin 2017 10;10:10. Epub 2017 Mar 10.

Department of Pathology and Lab Medicine, Western University, London, ON Canada.

Background: Alpha thalassemia/mental retardation X-linked syndrome (ATR-X) is caused by a mutation at the chromatin regulator gene . The mechanisms involved in the ATR-X pathology are not completely understood, but may involve epigenetic modifications. ATRX has been linked to the regulation of histone H3 and DNA methylation, while mutations in the gene may lead to the downstream epigenetic and transcriptional effects. Elucidating the underlying epigenetic mechanisms altered in ATR-X will provide a better understanding about the pathobiology of this disease, as well as provide novel diagnostic biomarkers.

Results: We performed genome-wide DNA methylation assessment of the peripheral blood samples from 18 patients with ATR-X and compared it to 210 controls. We demonstrated the evidence of a unique and highly specific DNA methylation "epi-signature" in the peripheral blood of ATRX patients, which was corroborated by targeted bisulfite sequencing experiments. Although genomically represented, differentially methylated regions showed evidence of preferential clustering in pericentromeric and telometric chromosomal regions, areas where ATRX has multiple functions related to maintenance of heterochromatin and genomic integrity.

Conclusion: Most significant methylation changes in the 14 genomic loci provide a unique epigenetic signature for this syndrome that may be used as a highly sensitive and specific diagnostic biomarker to support the diagnosis of ATR-X, particularly in patients with phenotypic complexity and in patients with gene sequence variants of unknown significance.
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http://dx.doi.org/10.1186/s13072-017-0118-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345252PMC
January 2018

The defining DNA methylation signature of Floating-Harbor Syndrome.

Sci Rep 2016 12 9;6:38803. Epub 2016 Dec 9.

Department of Pathology and Laboratory Medicine, Western University, 1151 Richmond Street, London, N6A 3K7, Canada.

Floating-Harbor syndrome (FHS) is an autosomal dominant genetic condition characterized by short stature, delayed osseous maturation, expressive language impairment, and unique facial dysmorphology. We previously identified mutations in the chromatin remodeling protein SRCAP (SNF2-related CBP Activator Protein) as the cause of FHS. SRCAP has multiple roles in chromatin and transcriptional regulation; however, specific epigenetic consequences of SRCAP mutations remain to be described. Using high resolution genome-wide DNA methylation analysis, we identified a unique and highly specific DNA methylation "epi-signature" in the peripheral blood of individuals with FHS. Both hyper and hypomethylated loci are distributed across the genome, preferentially occurring in CpG islands. Clonal bisulfite sequencing of two hypermethylated (FIGN and STPG2) and two hypomethylated (MYO1F and RASIP1) genes confirmed these findings. The identification of a unique methylation signature in FHS provides further insight into the biological function of SRCAP and provides a unique biomarker for this disorder.
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http://dx.doi.org/10.1038/srep38803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5146968PMC
December 2016

Clinical Validation of Fragile X Syndrome Screening by DNA Methylation Array.

J Mol Diagn 2016 11 29;18(6):834-841. Epub 2016 Aug 29.

Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada; London Regional Cancer Program, London Health Sciences Center, London, Ontario, Canada; Children's Health Research Institute, London Health Sciences Center, London, Ontario, Canada; Molecular Genetics Laboratory, London Health Sciences Center, London, Ontario, Canada. Electronic address:

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. It is most frequently caused by an abnormal expansion of the CGG trinucleotide repeat (>200 repeats) located in the promoter of the fragile X mental retardation gene (FMR1), resulting in promoter DNA hypermethylation and gene silencing. Current clinical tests for FXS are technically challenging and labor intensive, and may involve use of hazardous chemicals or radioisotopes. We clinically validated the Illumina Infinium HumanMethylation450 DNA methylation array for FXS screening. We assessed genome-wide and FMR1-specific DNA methylation in 32 males previously diagnosed with FXS, including nine with mosaicism, as well as five females with full mutation, and premutation carrier males (n = 11) and females (n = 11), who were compared to 300 normal control DNA samples. Our findings demonstrate 100% sensitivity and specificity for detection of FXS in male patients, as well as the ability to differentiate patients with mosaic methylation defects. Full mutation and premutation carrier females did not show FMR1 methylation changes. We have clinically validated this genome-wide DNA methylation assay as a cost- and labor-effective alternative for sensitive and specific screening for FXS, while ruling out the most common differential diagnoses of FXS, Prader-Willi syndrome, and Sotos syndrome in the same assay.
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http://dx.doi.org/10.1016/j.jmoldx.2016.06.005DOI Listing
November 2016

DNA methylation analysis in constitutional disorders: Clinical implications of the epigenome.

Crit Rev Clin Lab Sci 2016 12;53(3):147-65. Epub 2016 Jan 12.

a Departments of Pathology and Laboratory Medicine .

Genomic, chromosomal, and gene-specific changes in the DNA sequence underpin both phenotypic variations in populations as well as disease associations, and the application of genomic technologies for the identification of constitutional (inherited) or somatic (acquired) alterations in DNA sequence forms a cornerstone of clinical and molecular genetics. In addition to the disruption of primary DNA sequence, the modulation of DNA function by epigenetic phenomena, in particular by DNA methylation, has long been known to play a role in the regulation of gene expression and consequent pathogenesis. However, these epigenetic factors have been identified only in a handful of pediatric conditions, including imprinting disorders. Technological advances in the past decade that have revolutionized clinical genomics are now rapidly being applied to the emerging discipline of clinical epigenomics. Here, we present an overview of epigenetic mechanisms with a focus on DNA modifications, including the molecular mechanisms of DNA methylation and subtypes of DNA modifications, and we describe the classic and emerging genomic technologies that are being applied to this study. This review focuses primarily on constitutional epigenomic conditions associated with a spectrum of developmental and intellectual disabilities. Epigenomic disorders are discussed in the context of global genomic disorders, imprinting disorders, and single gene disorders. We include a section focused on integration of genetic and epigenetic mechanisms together with their effect on clinical phenotypes. Finally, we summarize emerging epigenomic technologies and their impact on diagnostic aspects of constitutional genetic and epigenetic disorders.
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http://dx.doi.org/10.3109/10408363.2015.1113496DOI Listing
November 2016

Chemotherapy-induced amenorrhea in patients with breast cancer with a BRCA1 or BRCA2 mutation.

J Clin Oncol 2013 Nov 26;31(31):3914-9. Epub 2013 Aug 26.

Adriana Valentini, Amy Finch, Ping Sun, and Steven A. Narod, Women's College Research Institute; Ellen Greenblatt, Centre for Fertility and Reproductive Health, Mount Sinai Hospital, University of Toronto, Toronto; Peter J. Ainsworth, London Regional Cancer Program, London, Ontario; Parviz Ghadirian, Research Center of the University of Montreal Hospital Centre, Montreal, Quebec; Charmaine Kim-Sing, BC Cancer Agency, Vancouver, British Columbia, Canada; Henry T. Lynch, Creighton University School of Medicine, Omaha, NE; Susan L. Neuhausen, Beckman Research Institute, City of Hope, Duarte, CA; Jan Lubiński and Tomasz Byrski, Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland; and Christian Singer, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Purpose: To determine the likelihood of long-term amenorrhea after treatment with chemotherapy in women with breast cancer who carry a BRCA1 or BRCA2 mutation.

Patients And Methods: We conducted a multicenter survey of 1,954 young women with a BRCA1 or BRCA2 mutation who were treated for breast cancer. We included premenopausal women who were diagnosed with invasive breast cancer between 26 and 47 years of age. We determined the age of onset of amenorrhea after breast cancer for women who were and were not treated with chemotherapy, alone or with tamoxifen. We considered chemotherapy-induced amenorrhea to have occurred when the patient experienced ≥ 2 years of amenorrhea, commencing within 2 years of initiating chemotherapy, with no resumption of menses.

Results: Of the 1,426 women who received chemotherapy, 35% experienced long-term amenorrhea. Of the 528 women who did not receive chemotherapy, 5.3% developed long-term amenorrhea. The probabilities of chemotherapy-induced amenorrhea were 7.2% for women diagnosed before age 30 years, 33% for women age 31 to 44 years, and 79% for women diagnosed after age 45 years (P trend < .001). The probability of induced amenorrhea was higher for women who received tamoxifen than for those who did not (52% v 29%; P < .001).

Conclusion: Age at treatment and use of tamoxifen are important predictors of chemotherapy-induced amenorrhea in women who carry a BRCA1 or BRCA2 mutation. The risk of induced long-term amenorrhea does not seem to be greater among mutation carriers than among women who do not carry a mutation.
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http://dx.doi.org/10.1200/JCO.2012.47.7893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805929PMC
November 2013

The impact of population-based screening studies on hemochromatosis screening practices.

Dig Dis Sci 2012 May;57(5):1420-2

Department of Medicine, University Hospital, University of Western Ontario, 339 Windermere Rd, London, ON N6A 5A5, Canada.

Objectives: To determine if community population screening studies for hemochromatosis affected HFE genetic screening practices in non-study populations.

Methods: An audit of all genetic testing for HFE mutations at London Health Sciences Center, London, Ontario, Canada from 1997 to 2010 was performed. The frequency of genetic testing and the frequency of C282Y homozygous cases identified during the years of the London Red Cross (1998-1999) and HEIRS (2000-2005) screening studies were compared with the corresponding frequencies in the specified years outside this range (1997-1998 and 2006-2010).

Results: An increase in HFE gene mutation testing is seen during the London Red Cross study, and the frequency of testing rose further during the HEIRS study. Genetic screening activity continued to increase in the years after publication of the HEIRS study. The proportion of patients with homozygosity for C282Y mutation remained relatively constant despite fluctuations in numbers of persons screened per annum.

Conclusions: The rise in HFE gene testing among non-study populations during the HH studies could be explained by the Hawthorne effect, a phenomenon referring to the improvement or modification of behavior by a population as a consequence of it being studied. In this case, we postulate that primary care physicians at our center performed more HFE gene tests for their patients as a consequence of being affected by knowledge of the screening studies. Despite a general increase in testing during and after completion of the studies, the total number of hemochromatosis cases (C282Y homozygotes) diagnosed per annum remained relatively constant.
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http://dx.doi.org/10.1007/s10620-011-2001-7DOI Listing
May 2012

Novel 95G>A (R32K) somatic mosaic connexin 32 mutation.

Muscle Nerve 2008 Nov;38(5):1510-1514

Department of Pathology, London Health Sciences Center, University of Western Ontario, London, Ontario, Canada.

Charcot-Marie-Tooth disease (CMT) is among the most common inherited disorders of the peripheral nervous system, and it is broadly categorized as demyelinating type 1 or axonal type 2 based on nerve conduction studies. Mutations in discrete genes usually segregate into a single phenotype. However, mutations in connexin 32 (Cx32) can produce both axonal and demyelinating CMT phenotypes. Although over 300 mutations have been described in Cx32, somatic mosaicism has only been reported once previously. We report a 39-year-old man who was referred for electrodiagnostic evaluation due to a history of bilateral carpal tunnel syndrome. His physical examination and electrodiagnostic findings demonstrated a mild sensorimotor axonal peripheral neuropathy. Sequencing of his Cx32 (GJB1) gene identified a guanine-to-adenine (G>A) transition at nucleotide position 95. This transition mutation involved approximately one-third of leukocyte-derived genomic DNA. This is the second reported case of somatic mosaicism, and it highlights the phenotypic diversity among CMTX patients.
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http://dx.doi.org/10.1002/mus.21145DOI Listing
November 2008

Infertility, treatment of infertility, and the risk of breast cancer among women with BRCA1 and BRCA2 mutations: a case-control study.

Cancer Causes Control 2008 Dec 29;19(10):1111-9. Epub 2008 May 29.

Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, ON, Canada.

Background: Women with a breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) mutation are at increased risk for developing breast and ovarian cancer. Various reproductive and hormonal factors have been shown to modify the risk of breast cancer. These studies suggest that estrogen exposure and deprivation are important in the etiology of hereditary cancer. Many patients are interested in the possibility of an adverse effect of fertility treatment on breast cancer risk. It is important to evaluate whether or not infertility per se or exposure to fertility medications increase the risk of breast cancer in genetically predisposed women.

Methods: We conducted a matched case-control study of 1,380 pairs of women with a BRCA1 or BRCA2 mutation to determine if a history of infertility, the use of fertility medications, or undergoing in vitro fertilization (IVF) were associated with and increased the risk of breast cancer.

Results: Sixteen percent of the study subjects reported having experienced a fertility problem and 4% had used a fertility medication. Women who had used a fertility medication were not at significantly increased risk of breast cancer (odds ratio [OR] = 1.21; 95% confidence interval [CI] = 0.81-1.82) compared to non-users. Furthermore, there was no risk associated with a history of use of a fertility medication when the subjects were stratified by parity: (OR = 1.29; 95% CI = 0.83-2.01 for nulliparous women and OR = 0.81; 95% CI = 0.30-2.22 for parous women).

Conclusions: The results of this study suggest that the use of fertility medications does not adversely affect the risk of breast cancer among BRCA mutation carriers. Given the small sizes of the exposed subgroups, these findings should be interpreted with caution and confirmatory studies are required.
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http://dx.doi.org/10.1007/s10552-008-9175-0DOI Listing
December 2008

A model for GFR alpha 4 function and a potential modifying role in multiple endocrine neoplasia 2.

Oncogene 2005 Feb;24(6):1091-7

Department of Pathology, Queen's University, Kingston, ON, Canada K7L 3N6.

Mutations of the RET proto-oncogene are found in the majority of patients with the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). A minority of cases, however, have no detectable RET mutation and there is considerable phenotypic variation within and among MEN 2 families with the same RET mutation, suggesting a role for other loci in this disease. A candidate for such a gene is glial cell line-derived neurotrophic factor receptor alpha 4 (GFRA4), which encodes a cell surface-bound co-receptor (GFR alpha 4) required for interaction of RET with its ligand persephin. The GFRA4 gene has multiple alternative splices leading to three distinct protein isoforms that are prominently expressed in thyroid. We postulated that mutations of GFRA4 contribute to MEN 2 in the absence of RET mutations or modify the RET mutation phenotype. We screened patients with MEN 2 or MEN 2-like phenotypes, with and without RET mutations, for variants of GFRA4. We identified 10 variants, one of which was over represented in, and two of which were found exclusively in, our patient populations. One of these was a single-base substitution upstream of the GFR alpha 4 coding region, where it may alter gene expression. The second was a 7 bp insertion, which results in a change in reading frame for all three GFR alpha 4 isoforms. This would cause a relative shift in membrane bound and soluble forms of GFR alpha 4, which would significantly alter the formation of RET signalling complexes. Our data suggest a model of wild-type GFR alpha 4 isoform expression that includes both activating and inhibiting co-receptors for RET.
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http://dx.doi.org/10.1038/sj.onc.1207826DOI Listing
February 2005

Genotype/Phenotype Correlations in X-Linked Dominant Charcot-Marie-Tooth Disease.

Ann N Y Acad Sci 1999 Oct;883(1):366-382

Department of Clinical Neurological Sciences, London Health Sciences Centre and The University of Western Ontario, London, Canada N6A 5A5Department of Neurological Sciences, Foothills Hospital and The University of Calgary, Alberta, CanadaDepartment of Neurology, New England Medical Center, Boston, Massachusetts, USADepartment of Biochemistry, London Health Sciences Centre and The Univeristy of Western Ontario, London, Canada N6A 5A5.

We have studied the relationship between genotype, clinical phenotype, and pathology in 13 families with dominant X-linked Charcot-Marie-Tooth (CMT) neuropathy. Connexin32 (Cx32) gene mutations were spread throughout the coding region and included eight missense mutations, one 8-bp deletion/4-bp insertion frame shifting mutation, two nonsense mutations, and one deletion of the entire coding sequence. One hundred sixteen affected CMTX patients (53 males and 63 females) and 63 unaffected, at-risk individuals were compared by neurological and electrophysiological examinations and analyzed by gender; nerve biopsies were available from seven index cases. It was found that mutations within all regions of the Cx32 gene coding sequence caused an identical clinical phenotype. Male CMTX patients were affected more severely and showed an age-dependent progression of clinical signs and of the pathology; there was, however, variability in the severity of disease expression, irrespective of age, among males within families of defined genotype. All but 10% of female CMTX patients had only mild signs. Motor nerve conduction velocities were moderately slowed (median nerve MNCV: males 34.5 ± 6.2 m/sec; females 45.8 ± 7.3 m/sec), and motor and sensory nerve amplitudes were reduced (median nerve CMAP: males 3.7 ± 3.7 mV; females 7.8 ± 3.4 mV), with electromyographic evidence of chronic denervation. Differences were significant between gender and between affected and unaffected individuals. In agreement with the electrophysiological observations, pathological studies showed evidence of paranodal demyelination and of a length-related axonal degeneration in motor and sensory nerve fibers. Correlations between genotype and clinical phenotype suggested that missense mutations located within the second transmembrane domain and/or cytoplasmic loop might be associated with milder clinical phenotype, and therefore might be less disruptive of Connexin32 gap junction function. Missense, chain-terminating, or deletion mutations in all other locations of the Connexin32 protein caused severe forms of CMTX and disease onset in the first decade. Observed variability of disease severity among males within kinships suggests the influence of other modifying factors.
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http://dx.doi.org/10.1111/j.1749-6632.1999.tb08598.xDOI Listing
October 1999
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