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Fabry disease is a multi-systemic X-linked genetic disorder which has progressive and deadly consequences for those it afflicts. Fabry disease symptoms are widely recognized as a substantive burden for affected males. In comparison, female heterozygotes have traditionally been viewed as relatively symptom-free, though a debate continues about whether and how much they suffer with the disease. Previous research suggests that females with Fabry disease may be triply disadvantaged in healthcare settings owing to: (1) disease rarity, (2) devalued carrier status, and (3) gender. The combined effects of these three factors suggest that female heterozygotes may suffer substantially with Fabry disease symptoms. A qualitative analysis of a brief disease-specific questionnaire provides supportive evidence. The female Fabry disease participants described experiencing significant symptoms that interfered with their lives. They also described unsatisfying experiences with healthcare professionals related to disease rarity, carrier status, and gender. The results of this study corroborate the suggestion that this triple disadvantage exists and may preclude appropriate management and treatment of females with Fabry disease. The role of healthcare professionals, including genetic counselors, in remedying this disadvantage is reviewed. [ABSTRACT FROM AUTHOR]

Discusses the abstract of the study 'Genetic Counseling for Double BRCA Mutation Carriers: A Case Series,' presented at the 21st Annual Education Conference of the National Society of Genetic Counselors held in Phoenix, Arizona in November 2002.

Abstract Background Signalling by fibroblast growth factor receptor type 2 (FGFR2) normally involves a tissue-specific alternative splice choice between two exons (IIIb and IIIc), which generates two receptor isoforms (FGFR2b and FGFR2c respectively) with differing repertoires of FGF-binding specificity. Here we describe a unique chimeric IIIb/c exon in a patient with Apert syndrome, generated by a non-allelic homologous recombination event. Case Presentation We present a child with Apert syndrome in whom routine genetic testing had excluded the FGFR2 missense mutations commonly associated with this disorder. The patient was found to harbour a heterozygous 1372 bp deletion between FGFR2 exons IIIb and IIIc, apparently originating from recombination between 13 bp of identical DNA sequence present in both exons. The rearrangement was not present in the unaffected parents. Conclusions Based on the known pathogenesis of Apert syndrome, the chimeric FGFR2 protein is predicted to act in a dominant gain-of-function manner. This is likely to result from its expression in mesenchymal tissues, where retention of most of the residues essential for FGFR2b binding activity would result in autocrine activation. This report adds to the repertoire of rare cases of Apert syndrome for which a pathogenesis based on atypical FGFR2 rearrangements can be demonstrated.

Discusses the abstract of the study 'Parent & Teacher Concerns of School-Age Children With Isolated Cleft Lip and Palate or Cleft Palate,' presented at the 21st Annual Education Conference of the National Society of Genetic Counselors held in Phoenix, Arizona in November 2002.

Objective: To report the clinical and novel electrophysiological features in a child with POLG-related sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO)., Methods: The proband, a male child of Indian descent, underwent serial systemic and ophthalmological evaluations from birth until 14 years of age. Eye examinations included visual acuity and extraocular movement assessments, fundus photography, spectral domain optical coherence tomography and full-field electroretinography (ERG). Detailed genetic testing was also performed., Results: The child carried a homozygous mutation in POLG (c.911T > G/p.Leu304Arg) and manifested systemic features such as seizures, headaches, areflexia, hypotonia, myopathy and vomiting. The child's distance visual acuity was 0.50 and 0.40 LogMAR in the right and left eyes, respectively. Bilateral ophthalmoplegia and ptosis were observed at 5 years of age. The dark-adapted (DA) ERG responses to 2.29 cd s m -2 and 7.6 cd s m -2 stimuli showed a markedly reduced b/a ratio; an electronegative configuration was noted to a DA 7.6 ERG., Conclusion: This is the first documented case of an electronegative ERG in a POLG-related disorder consistent with generalized rod ON-bipolar dysfunction. The rest of the proband's systemic and ophthalmological features were consistent with SANDO but some features overlapped with other POLG-related disorders such as Alpers-Huttenlocher syndrome and autosomal dominant progressive external ophthalmoplegia demonstrating the wide phenotypic overlap expected due to POLG mutations.

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

Ocular anomalies have been frequently reported in Noonan syndrome. Anterior segment anomalies have been described in 57% of PTPN11 positive patients, with the most common findings being corneal changes and in particular, prominent corneal nerves and cataracts. We report on a neonate with a confirmed PTPN11 mutation and ocular findings consistent with Axenfeld anomaly. The patient initially presented with non-immune hydrops and subsequently developed hypertrophic cardiomyopathy and dysmorphic features typical of Noonan syndrome. While a pathogenic mutation in PTPN11 was confirmed, prior testing for the two common genes associated with Axenfeld-Rieger syndrome, PITX2, and FOXC1 was negative. This finding expands the spectrum of anterior chamber anomalies seen in Noonan syndrome and perhaps suggests a common neural crest related mechanism that plays a critical role in the development of the eye and other organs., (© 2014 Wiley Periodicals, Inc.)

Hearing impairment is common in individuals with branchio-oculo-facial (BOF) syndrome. The majority of described individuals have conductive hearing impairment due to malformed ossicles and/or external canal stenosis or atresia, although a sensorineural component to the hearing impairment in BOF syndrome is increasingly being reported. Sophisticated computed tomography (CT) of the temporal bone has revealed middle and inner ear malformations in three previous reports. We present middle and inner ear abnormalities in three additional individuals with mutation-proven BOF syndrome. We suggest that temporal bone CT imaging be included in the medical workup of a child with BOF syndrome, in order to guide management., (Copyright © 2012 Wiley Periodicals, Inc.)

Pulmonary arteriovenous malformations (PAVMs) can cause stroke, brain abscess or life-threatening haemorrhage. Most PAVMs are associated with hereditary haemorrhagic telangiectasia (HHT). The aim of the present study was to describe the clinical presentation and treatment outcomes of those with idiopathic PAVMs, which has not previously been described in the literature. Patients with idiopathic PAVMs were identified at our HHT centre. Retrospective review of charts and imaging were performed. 20 patients were identified with idiopathic PAVMs. The most common symptoms reported were dyspnoea and migraines (50 and 30% of patients, respectively). Previous complications of PAVMs included haemoptysis (20%), stroke (20%) and brain abscess (5%). A total of 28 focal PAVMs were identified. Most patients (80%) had a solitary PAVM. 13 out of 28 PAVMs (46%) were located in the lower lobes. Most were simple and fistulous rather than complex and plexiform. Transcatheter embolotherapy was performed in 17 patients and was successful in improving oxygenation in all cases. The clinical manifestations and complications of idiopathic PAVMs are similar to those associated with HHT. Idiopathic PAVMs are anatomically similar to HHT-related PAVMs except for a greater number of solitary PAVMs and a lack of lower lobe predominance. Transcatheter embolotherapy is a safe and effective method for treating idiopathic PAVMs.

Branchio-oculo-facial syndrome (BOFS; OMIM#113620) is a rare autosomal dominant craniofacial disorder with variable expression. Major features include cutaneous and ocular abnormalities, characteristic facies, renal, ectodermal, and temporal bone anomalies. Having determined that mutations involving TFAP2A result in BOFS, we studied a total of 30 families (41 affected individuals); 26/30 (87%) fulfilled our cardinal diagnostic criteria. The original family with the 3.2 Mb deletion including the TFAP2A gene remains the only BOFS family without the typical CL/P and the only family with a deletion. We have identified a hotspot region in the highly conserved exons 4 and 5 of TFAP2A that harbors missense mutations in 27/30 (90%) families. Several of these mutations are recurrent. Mosaicism was detected in one family. To date, genetic heterogeneity has not been observed. Although the cardinal criteria for BOFS have been based on the presence of each of the core defects, an affected family member or thymic remnant, we documented TFAP2A mutations in three (10%) probands in our series without a classic cervical cutaneous defect or ectopic thymus. Temporal bone anomalies were identified in 3/5 patients investigated. The occurrence of CL/P, premature graying, coloboma, heterochromia irides, and ectopic thymus, are evidence for BOFS as a neurocristopathy. Intrafamilial clinical variability can be marked. Although there does not appear to be mutation-specific genotype-phenotype correlations at this time, more patients need to be studied. Clinical testing for TFAP2A mutations is now available and will assist geneticists in confirming the typical cases or excluding the diagnosis in atypical cases., (Copyright © 2010 Wiley-Liss, Inc.)

Interstitial deletions involving 6q11-q14 have been reported in less than 20 patients, with the breakpoints studied by G-banding alone. We report on seven patients with 6q11-q14 interstitial deletions of variable size. The breakpoints were studied by G-banding, dual-color BAC-FISH and SNP array. The results showed the molecular breakpoints differed significantly from the ones obtained from G-banding. The breakpoints studied by BAC-FISH were consistent with the ones from SNP array. Some characteristics from this cohort are consistent with previous reports, but many typical features are lacking in our patients. The cardinal features of 6q11-q14 interstitial deletions in this cohort include: umbilical hernia, hypotonia, short stature, characteristic facial features of upslanting palpebral fissures, low set and/or dysplastic ears, high arched palate, urinary tract anomalies, and skeletal/limb anomalies., (2009 Wiley-Liss, Inc.)

22q11 Deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans, occurring with an incidence of 1 in 4,000. In most cases the submicroscopic deletion spans 3 Mb, but there are a number of other overlapping and non-overlapping deletions that generate a similar phenotype. The majority of the 22q11.2 microdeletions can be ascertained using a standard fluorescence in situ hybridization (FISH) assay probing for TUPLE1 or N25 on 22q11.2. However, this test fails to detect deletions that are either proximal or distal to the FISH probes, and does not provide any information about the length of the deletion. In order to increase the detection rate of 22q11.2 deletion and to better characterize the size and position of such deletions we undertook a study of 22q11.2 cases using multiplex ligation dependent probe amplification (MLPA). We used MLPA to estimate the size of the 22q11.2 deletions in 51 patients positive for TUPLE1 or N25 (FISH) testing, and to investigate 12 patients with clinical features suggestive of 22q11DS and negative FISH results. MLPA analysis confirmed a microdeletion in all 51 FISH-positive samples as well as microduplications in three samples. Further, it allowed us to delineate deletions not previously detected using standard clinical FISH probes in 2 of 12 subjects with clinical features suggestive of 22q11DS. We conclude that MLPA is a cost-effective and accurate diagnostic tool for 22q11DS with a higher sensitivity than FISH alone. Additional advantages of MLPA testing in our study included determination of deletion length and detection of 22q11.2 duplications. (c) 2007 Wiley-Liss, Inc., ((c) 2007 Wiley-Liss, Inc.)

Background: The clinical onset of Fabry disease, a rare, X-linked, multisystemic disorder, is marked by neuropathic pain. Males suffer extensively from this disease. Females, as genetic 'carriers', have traditionally been viewed as either asymptomatic or mildly afflicted with this disease., Objectives: To describe Fabry-related pain and compare experiences between the sexes. Patients' perceptions of physician pain assessments were also examined., Methods: A disease-specific questionnaire was accessible on-line (www.fabry.org) and mailed to 552 members of a Fabry disease support group., Results: The response rate was 14.3% for the support group-based mail questionnaire. Females (58.0%) were significantly older (mean +/- SD 45.9+/-13.5 years) than males (mean +/- SD 40.0+/-12.1; t [86]=-2.11, P<0.05). Females were diagnosed with Fabry disease later (31.1+/-14.0 years) than males (24.2+/-11.9 years; t [86]=-2.43, P<0.05). Females (mean score for pain disability rating 3.0+/-1.4) suffered more extensive disability from migraine pain (mean score 2.2+/-1.3; F [1, 74]=45.0, P<0.005), and, unlike males, did not exhibit a decline in pain intensity with disease duration. Satisfaction with physician pain assessments was moderate., Conclusions: Contrary to the traditional view of females as carriers, females with Fabry disease experienced intense disease-related pain; pain produced comparable distress and impairment in both sexes. The diagnostic delay and absence of a decline in pain symptoms over time in females suggest additional disease burden. Females may be triply disadvantaged in the health care system due to disease rarity, devalued carrier status and sex.