Publications by authors named "Victoria Mok Siu"

27 Publications

  • Page 1 of 1

Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders.

Genet Med 2021 Feb 5. Epub 2021 Feb 5.

Amsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.

Purpose: We describe the clinical implementation of genome-wide DNA methylation analysis in rare disorders across the EpiSign diagnostic laboratory network and the assessment of results and clinical impact in the first subjects tested.

Methods: We outline the logistics and data flow between an integrated network of clinical diagnostics laboratories in Europe, the United States, and Canada. We describe the clinical validation of EpiSign using 211 specimens and assess the test performance and diagnostic yield in the first 207 subjects tested involving two patient subgroups: the targeted cohort (subjects with previous ambiguous/inconclusive genetic findings including genetic variants of unknown clinical significance) and the screening cohort (subjects with clinical findings consistent with hereditary neurodevelopmental syndromes and no previous conclusive genetic findings).

Results: Among the 207 subjects tested, 57 (27.6%) were positive for a diagnostic episignature including 48/136 (35.3%) in the targeted cohort and 8/71 (11.3%) in the screening cohort, with 4/207 (1.9%) remaining inconclusive after EpiSign analysis.

Conclusion: This study describes the implementation of diagnostic clinical genomic DNA methylation testing in patients with rare disorders. It provides strong evidence of clinical utility of EpiSign analysis, including the ability to provide conclusive findings in the majority of subjects tested.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-01096-4DOI Listing
February 2021

Detection of a DNA Methylation Signature for the Intellectual Developmental Disorder, X-Linked, Syndromic, Armfield Type.

Int J Mol Sci 2021 Jan 23;22(3). Epub 2021 Jan 23.

Greenwood Genetic Center, Greenwood, SC 29646, USA.

A growing number of genetic neurodevelopmental disorders are known to be associated with unique genomic DNA methylation patterns, called episignatures, which are detectable in peripheral blood. The intellectual developmental disorder, X-linked, syndromic, Armfield type (MRXSA) is caused by missense variants in . Functional studies revealed the pathogenesis to be a spliceosomopathy that is characterized by atypical mRNA processing during development. In this study, we assessed the peripheral blood specimens in a cohort of individuals with MRXSA and detected a unique and highly specific DNA methylation episignature associated with this disorder. We used this episignature to construct a support vector machine model capable of sensitive and specific identification of individuals with pathogenic variants in . This study contributes to the expanding number of genetic neurodevelopmental disorders with defined DNA methylation episignatures, provides an additional understanding of the associated molecular mechanisms, and further enhances our ability to diagnose patients with rare disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22031111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865843PMC
January 2021

Clinical and technical assessment of MedExome vs. NGS panels in patients with suspected genetic disorders in Southwestern Ontario.

J Hum Genet 2021 May 23;66(5):451-464. Epub 2020 Oct 23.

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

The adaptation of a broad genomic sequencing approach in the clinical setting has been accompanied by considerations regarding the clinical utility, technical performance, and diagnostic yield compared to targeted genetic approaches. We have developed MedExome, an integrated framework for sequencing, variant calling (SNVs, Indels, and CNVs), and clinical assessment of ~4600 medically relevant genes. We compared the technical performance of MedExome with the whole-exome and targeted gene-panel sequencing, assessed the reasons for discordance, and evaluated the added clinical yield of MedExome in a cohort of unresolved subjects suspected of genetic disease. Our analysis showed that despite a higher average read depth in panels (3058 vs. 855), MedExome yielded full coverage of the enriched regions (>20X) and 99% variant concordance rate with panels. The discordance rate was associated with low-complexity regions, high-GC content, and low allele fractions, observed in both platforms. MedExome yielded full sensitivity in detecting clinically actionable variants, and the assessment of 138 patients with suspected genetic conditions resulted in 76 clinical reports (31 full [22.1%], 3 partial, and 42 uncertain/possible molecular diagnoses). MedExome sequencing has comparable performance in variant detection to gene panels. Added diagnostic yield justifies expanded implementation of broad genomic approaches in unresolved patients; however, cost-benefit and health systems impact warrants assessment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-020-00860-3DOI Listing
May 2021

A novel homozygous variant in REN in a family presenting with classic features of disorders involving the renin-angiotensin pathway, without renal tubular dysgenesis.

Am J Med Genet A 2020 10 17;182(10):2284-2290. Epub 2020 Aug 17.

Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

Autosomal recessively inherited pathogenic variants in genes associated with the renin-angiotensin-aldosterone system (RAAS) result in early onset oligohydramnios and clinical features of the Potter sequence, typically in association with proximal renal tubules dysgenesis. We describe two siblings and a first cousin who had severe oligohydramnios in the second trimester, and presented at birth with loose skin, wide fontanelles and sutures, and pulmonary insufficiency. Two had refractory hypotension during their brief lives and one received palliative care after birth. All were found to have a homozygous nonsense variant, REN: c.891delG; p.Tyr287*, on exome sequencing. Autopsy limited to the genitourinary system in two of the children revealed normal renal tubular histology in both. Immunoblotting confirmed diminished expression of renin within cultured skin fibroblasts. To our knowledge, this is the first identification of an association between biallelic variants in REN and oligohydramnios in the absence of renal tubular dysgenesis. Due to its role in the RAAS, it has previously been proposed that the decreased expression of REN results in hypotension, ischemia, and decreased urine production. We suggest sequencing of genes in the RAAS, including REN, should be considered in cases of severe early onset oligohydramnios, even when renal morphology and histology are normal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61780DOI Listing
October 2020

Transient hyponatremia of prematurity caused by mild Bartter syndrome type II: a case report.

BMC Pediatr 2020 06 26;20(1):311. Epub 2020 Jun 26.

Department of Pediatrics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond Street, London, ON, N6A5C1, Canada.

Background: Bartter syndrome subtypes are a group of rare renal tubular diseases characterized by impaired salt reabsorption in the tubule, specifically the thick ascending limb of Henle's loop. Clinically, they are characterized by the association of hypokalemic metabolic alkalosis, hypercalciuria, nephrocalcinosis, increased levels of plasma renin and aldosterone, low blood pressure and vascular resistance to angiotensin II. Bartter syndrome type II is caused by mutations in the renal outer medullary potassium channel (ROMK) gene (KCNJ1), can present in the newborn period and typically requires lifelong therapy.

Case Presentation: We describe a case of a prematurely born female infant presenting with antenatal polyhydramnios, and postnatal dehydration and hyponatremia. After 7 weeks of sodium supplementation, the patient demonstrated complete resolution of her hyponatremia and developed only transient metabolic alkalosis at 2 months of age but continues to be polyuric and exhibits hypercalciuria, without development of nephrocalcinosis. She was found to have two pathogenic variants in the KCNJ1 gene: a frameshift deletion, p.Glu334Glyfs*35 and a missense variant, p. Pro110Leu. While many features of classic ROMK mutations have resolved, the child does have Bartter syndrome type II and needs prolonged pediatric nephrology follow-up.

Conclusion: Transient neonatal hyponatremia warrants a multi-system workup and genetic variants of KCNJ1 should be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12887-020-02214-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318402PMC
June 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058829PMC
March 2020

Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature.

Clin Epigenetics 2020 01 7;12(1). Epub 2020 Jan 7.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy.

Background: We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern.

Results: Methylome analysis from peripheral blood samples of six affected subjects led us to identify a specific hypomethylated profile. This "episignature" was enriched for genes involved in neuronal system development and function. A computational classifier yielded full sensitivity and specificity in detecting subjects with Rahman syndrome. Applying this model to a cohort of undiagnosed probands allowed us to reach diagnosis in one subject.

Conclusions: We demonstrate an epigenetic signature in subjects with Rahman syndrome that can be used to reach molecular diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-019-0804-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947958PMC
January 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2019.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451739PMC
April 2019

Homozygous/compound heterozygote RYR1 gene variants: Expanding the clinical spectrum.

Am J Med Genet A 2019 03 16;179(3):386-396. Epub 2019 Jan 16.

The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

The ryanodine receptor 1 (RYR1) is a calcium release channel essential for excitation-contraction coupling in the sarcoplasmic reticulum of skeletal muscles. Dominant variants in the RYR1 have been well associated with the known pharmacogenetic ryanodinopathy and malignant hyperthermia. With the era of next-generation gene sequencing and growing number of causative variants, the spectrum of ryanodinopathies has been evolving with dominant and recessive variants presenting with RYR1-related congenital myopathies such as central core disease, minicore myopathy with external ophthalmoplegia, core-rod myopathy, and congenital neuromuscular disease. Lately, the spectrum was broadened to include fetal manifestations, causing a rare recessive and lethal form of fetal akinesia deformation sequence syndrome (FADS)/arthrogryposis multiplex congenita (AMC) and lethal multiple pterygium syndrome. Here we broaden the spectrum of clinical manifestations associated with homozygous/compound heterozygous RYR1 gene variants to include a wide range of manifestations from FADS through neonatal hypotonia to a 35-year-old male with AMC and PhD degree. We report five unrelated families in which three presented with FADS. One of these families was consanguineous and had three affected fetuses with FADS, one patient with neonatal hypotonia who is alive, and one individual with AMC who is 35 years old with normal intellectual development and uses a wheelchair. Muscle biopsies on these cases demonstrated a variety of histopathological abnormalities, which did not assist with the diagnostic process. Neither the affected living individuals nor the parents who are obligate heterozygotes had history of malignant hyperthermia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61025DOI Listing
March 2019

Mutation Interrupts Nucleolin-mTOR-P70S6K Signaling in Rett Syndrome Patients.

Front Genet 2018 19;9:635. Epub 2018 Dec 19.

Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

Rett syndrome (RTT) is a severe and rare neurological disorder that is caused by mutations in the X-linked (methyl CpG-binding protein 2) gene. MeCP2 protein is an important epigenetic factor in the brain and in neurons. In -deficient neurons, nucleoli structures are compromised. Nucleoli are sites of active ribosomal RNA () transcription and maturation, a process mainly controlled by nucleolin and mechanistic target of rapamycin (mTOR)-P70S6K signaling. Currently, it is unclear how nucleolin--mTOR-P70S6K signaling from RTT cellular model systems translates into human RTT brain. Here, we studied the components of nucleolin--mTOR-P70S6K signaling in the brain of RTT patients with common T158M and R255X mutations. Immunohistochemical examination of T158M brain showed disturbed nucleolin subcellular localization, which was absent in -deficient homozygous male or heterozygote female mice, compared to wild type (WT). We confirmed by Western blot analysis that nucleolin protein levels are altered in RTT brain, but not in -deficient mice. Further, we studied the expression of transcripts in -deficient mice and RTT patients, as downstream molecules that are controlled by nucleolin. By data mining of published ChIP-seq studies, we showed MeCP2-binding at the multi-copy genes in the mouse brain, suggesting that might be a direct MeCP2 target gene. Additionally, we observed compromised mTOR-P70S6K signaling in the human RTT brain, a molecular pathway that is upstream of -nucleolin molecular conduits. RTT patients showed significantly higher phosphorylation of active mTORC1 or mTORC2 complexes compared to age- and sex-matched controls. Correlational analysis of mTORC1/2-P70S6K signaling pathway identified multiple points of deviation from the control tissues that may result in abnormal ribosome biogenesis in RTT brain. To our knowledge, this is the first report of deregulated nucleolin--mTOR-P70S6K signaling in the human RTT brain. Our results provide important insight toward understanding the molecular properties of human RTT brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2018.00635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305968PMC
December 2018

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-07193-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244416PMC
November 2018

Using eye-tracking technology for communication in Rett syndrome: perceptions of impact.

Augment Altern Commun 2018 09 27;34(3):230-241. Epub 2018 Apr 27.

b Research Department , Thames Valley Children's Centre , London , Ontario , Canada.

Studies have investigated the use of eye-tracking technology to assess cognition in individuals with Rett syndrome, but few have looked at this access method for communication for this group. Loss of speech, decreased hand use, and severe motor apraxia significantly impact functional communication for this population. Eye gaze is one modality that may be used successfully by individuals with Rett syndrome. This multiple case study explored whether using eye-tracking technology, with ongoing support from a team of augmentative and alternative communication (AAC) therapists, could help four participants with Rett syndrome meet individualized communication goals. Two secondary objectives were to examine parents' perspectives on (a) the psychosocial impact of their child's use of the technology, and (b) satisfaction with using the technology. All four participants were rated by the treating therapists to have made improvement on their goals. According to both quantitative findings and descriptive information, eye-tracking technology was viewed by parents as contributing to participants' improved psychosocial functioning. Parents reported being highly satisfied with both the device and the clinical services received. This study provides initial evidence that eye-tracking may be perceived as a worthwhile and potentially satisfactory technology to support individuals with Rett syndrome in communicating. Future, more rigorous research that addresses the limitations of a case study design is required to substantiate study findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/07434618.2018.1462848DOI Listing
September 2018

PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature.

J Med Genet 2018 02 2;55(2):104-113. Epub 2017 Nov 2.

Department of Pediatric Neurology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.

Background: De novo mutations in have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia.

Objectives: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations.

Methods: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of -derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes.

Results: We report mutations in (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes.

Conclusion: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2017-104946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800346PMC
February 2018

Choosing Wisely Canada: The Canadian College of Medical Geneticists' (CCMG) list of five items physicians and patients should question.

J Med Genet 2018 02 19;55(2):86-88. Epub 2017 Aug 19.

Department of Medical Genetics, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2017-104924DOI Listing
February 2018

A fourth case of Feingold syndrome type 2: psychiatric presentation and management.

BMJ Case Rep 2014 Nov 12;2014. Epub 2014 Nov 12.

Brain and Mind Institute, University of Western Ontario, London, Ontario, Canada Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada.

Feingold syndrome (FGLDS1) is an autosomal dominant disorder caused by mutations in the MYCN oncogene on the short arm of chromosome 2 (2p24.1). It is characterised by microcephaly, digital abnormalities, oesophageal and duodenal atresias, and often learning disability or mental retardation. In 2011, individuals sharing the skeletal abnormalities of FGLDS1 but lacking mutations in MYCN, were found to harbour hemizygous deletions of the MIR17HG gene on chromosome 13q31.3. These individuals share many of the characteristics of FGLDS1 except for gastrointestinal atresia. The condition was termed Feingold syndrome type 2 (FGLDS2). We describe the presentation and management of a fourth known case of FGLDS2 in an 18-year-old girl with microcephaly, short stature, mildly dysmorphic features, digital malformations and significant cognitive and psychiatric symptoms. Comparative genomic hybridisation array testing confirmed a 7.4 Mb microdeletion in chromosome region 13q31.1q.31.3 corresponding to the MIR17HG gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr-2014-207501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244445PMC
November 2014

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.

Eur J Hum Genet 2015 Mar 23;23(3):292-301. Epub 2014 Jul 23.

McMaster University, Hamilton, Ontario, Canada.

Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode β- and γ-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2014.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326722PMC
March 2015

Congenital myotonic dystrophy: Canadian population-based surveillance study.

J Pediatr 2013 Jul 14;163(1):120-5.e1-3. Epub 2013 Feb 14.

Department of Pediatrics, Shulich School of Medicine, London Health Sciences Center, University of Western Ontario, London, Ontario, Canada.

Objectives: To determine the incidence and neonatal morbidity and mortality of congenital myotonic dystrophy (CDM) in Canada.

Study Design: The study has 2 phases. A 5-year prospective monthly surveillance of incident cases of CDM conducted via the Canadian Pediatric Surveillance Program, from March 1, 2005-February 28, 2010, and a 5-year cohort study of eligible incident cases, which is ongoing and not the subject of this report.

Results: A total of 121 cases were reported, with 38 confirmed as CDM. The incidence of CDM in Canada is 2.1/100,000 (1/47,619) live births. The cases were reported from 8 provinces and 1 territory. The highest reported incidence was Ontario with 15, followed by British Columbia with 7, and Quebec with 6. External validation of cases was performed. The trinucleotide repeat level varied from 550-3100. Twenty-two (58%) of the children were the index cases for their families. Seventeen children are currently enrolled in the ongoing cohort study.

Conclusion: Surveillance and prospective examination of CDM at a population level is important, as the impact of this rare disease is systemic, chronic, and associated with significant morbidity and mortality throughout childhood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpeds.2012.12.070DOI Listing
July 2013

Situs inversus totalis and a novel ZIC3 mutation in a family with X-linked heterotaxy.

Congenit Heart Dis 2013 Mar-Apr;8(2):E36-40. Epub 2011 Dec 16.

Department of Pediatrics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

Disorders of laterality consist of a complex set of malformations resulting from failure to establish normal asymmetry along the left-right axis, and include both heterotaxy and situs inversus totalis. Zinc fingers in cerebellum 3 (ZIC3) was the first gene to be definitively associated with heterotaxy syndromes in humans (OMIM #306955), with 13 mutations previously described in both familial and sporadic cases. We now report the clinical and molecular characterization of a five-generation family originally reported in 1974 as having X-linked dextrocardia. Longitudinal follow-up revealed that this family has X-linked heterotaxy due to a missense mutation, c.1048A>G(R350G), in the third zinc finger domain of ZIC3. The pedigree demonstrates the first reported case of situs inversus totalis associated with a ZIC3 mutation in a male and the second reported case of incomplete penetrance in an unaffected transmitting male, as well as a wide range of phenotypes of varying severity. Several affected members also exhibit renal and hindgut malformations, consistent with previously reported secondary features in ZIC3 mutations. The spectrum of features in this family emphasizes the importance of thorough molecular and imaging studies in both sporadic and familial cases of heterotaxy to ensure accurate prenatal diagnosis and recurrence risk counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1747-0803.2011.00602.xDOI Listing
September 2013

Fetal pads as a clue to the diagnosis of Pitt-Hopkins syndrome.

Am J Med Genet A 2011 Jul 10;155A(7):1685-9. Epub 2011 Jun 10.

Manchester Biomedical Research Centre, MAHSC, St Mary's Hospital, UK.

Pitt-Hopkins syndrome (PHS) is characterized by severe mental retardation, characteristic facial features including a wide mouth and intermittent overbreathing. It is due to abnormalities of the TCF4 gene at 18q21.1 and over 50 cases have now been reported in the literature. The clinical features overlap significantly with those of Angelman, Rett, and Mowat-Wilson syndromes. We have observed prominent fetal pads as a feature in several individuals with PHS and suggested that this is a useful clinical sign which helps to distinguish PHS from other conditions in the differential diagnosis and may guide genetic testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.34055DOI Listing
July 2011

Amish microcephaly: Long-term survival and biochemical characterization.

Am J Med Genet A 2010 Jul;152A(7):1747-51

Department of Pediatrics, University of Western Ontario, London, Ontario, Canada.

Amish microcephaly (MCPHA, OMIM #607196) is a metabolic disorder that has been previously characterized by severe infantile lethal congenital microcephaly and alpha-ketoglutaric aciduria. All reported patients have been from the Pennsylvania Amish community and homozygous for a p.Gly177Ala mutation in SLC25A19. We present a further male patient with MCPHA born to distantly consanguineous parents in Ontario, Canada with Amish ancestors. Microcephaly was evident at 21 weeks gestation on ultrasound. At birth, the facial appearance and brain MRI scan were characteristic of MCPHA, with the additional features of partial agenesis of the corpus callosum and a closed spinal dysraphic state. Urine levels of alpha-ketoglutaric acid were normal at birth and during metabolic crisis, but were markedly elevated during a time of metabolic stability. A severe lactic acidosis was present during metabolic crises and responded to treatment with a high fat diet. At age 7 years, the child is healthy but has severe microcephaly and profound developmental delay. SLC25A19 has been described as a mitochondria inner membrane transporter for both deoxynucleotides and thiamine pyrophosphate (TPP). The biochemical phenotype of MCPHA may be attributable to decreased activity of the three mitochondrial enzymes that require TPP as a cofactor: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched chain amino acid dehydrogenase. We confirm that alpha-ketoglutaric aciduria is not a constant finding in MCPHA and suggest that a persistent lactic acidemia may be more common. The diagnosis should be considered in patients with severe congenital microcephaly, especially in association with lissencephaly, dysgenesis of the corpus callosum, or a spinal dysraphic state.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.33373DOI Listing
July 2010

Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea.

Am J Hum Genet 2009 Feb 29;84(2):188-96. Epub 2009 Jan 29.

Department of Pediatrics II, Innsbruck Medical University, A-6020 Innsbruck, Austria.

Autosomal-recessive congenital sodium diarrhea (CSD) is characterized by perinatal onset of a persistent watery diarrhea with nonproportionally high fecal sodium excretion. Defective jejunal brush-border Na(+)/H(+) exchange has been reported in three sporadic patients, but the molecular basis of the disease has not been elucidated. We reviewed data from a large cohort of CSD patients (n = 24) and distinguished CSD associated with choanal or anal atresia, hypertelorism, and corneal erosions--i.e., a syndromic form of CSD--occurring in ten families from an isolated form--i.e., classic CSD--presenting in seven families. Patients from both groups have a high risk of mortality due to immediate electrolyte imbalances and complications from long-term parenteral nutrition in the first years of life, but survivors can eventually adapt to partial or complete enteral nutrition. A genome-wide SNP scan was applied and identified a homozygous c.593-1G-->A splicing mutation in SPINT2, encoding a Kunitz-type serine-protease inhibitor, in one extended kindred with syndromic CSD. The same mutation and four distinct, homozygous or compound heterozygous mutations (p.Y163C, c.1A-->T, c.337+2T-->C, c.553+2T-->A) were identified in all syndromic patients. No SPINT2 mutations were found in classic-CSD patients. SPINT2 mutations were associated with loss of protein synthesis or failure to inhibit the serine protease trypsin in vitro. We delineate syndromic CSD as a distinct disease entity caused by SPINT2 loss-of-function mutations. SPINT2 mutations might lead to an excess of yet unknown serine protease activity in affected tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2009.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668003PMC
February 2009

Breakpoint Associated with a novel 2.3 Mb deletion in the VCFS region of 22q11 and the role of Alu (SINE) in recurring microdeletions.

BMC Med Genet 2006 Mar 2;7:18. Epub 2006 Mar 2.

Department of Biology, University of Western Ontario, London, Ontario, N6A 5B7, Canada .

Background: Chromosome 22q11.2 region is highly susceptible to rearrangement, specifically deletions that give rise to a variety of genomic disorders including velocardiofacial or DiGeorge syndrome. Individuals with this 22q11 microdeletion syndrome are at a greatly increased risk to develop schizophrenia.

Methods: Genotype analysis was carried out on the DNA from a patient with the 22q11 microdeletion using genetic markers and custom primer sets to define the deletion. Bioinformatic analysis was performed for molecular characterization of the deletion breakpoint sequences in this patient.

Results: This 22q11 deletion patient was established to have a novel 2.3 Mb deletion with a proximal breakpoint located between genetic markers RH48663 and RH48348 and a distal breakpoint between markers D22S1138 and SHGC-145314. Molecular characterization of the sequences at the breakpoints revealed a 270 bp shared sequence of the breakpoint regions (SSBR) common to both ends that share >90% sequence similarity to each other and also to short interspersed nuclear elements/Alu elements.

Conclusion: This Alu sequence like SSBR is commonly in the proximity of all known deletion breakpoints of 22q11 region and also in the low copy repeat regions (LCRs). This sequence may represent a preferred sequence in the breakpoint regions or LCRs for intra-chromosomal homologous recombination mechanisms resulting in common 22q11 deletion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2350-7-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413517PMC
March 2006

Bilateral complete isolated cryptophthalmos: a case report.

Ophthalmic Genet 2005 Dec;26(4):185-9

University of Western Ontario, London, Ontario, Canada.

Cryptophthalmos is a condition of congenital eyelid malformation most commonly accompanied by syndactyly, urogenital anomalies, and cognitive impairments as in Fraser syndrome. We report on a patient with characteristic features consistent with autosomal dominant bilateral complete isolated cryptophthalmos. This patient represents only the sixth documented case of bilateral complete isolated cryptophthalmos. Defining characteristics of this variety are discussed, including bilateral central dimpling over the globes, normal eyebrow growth, and the absence of cognitive impairment. We introduce phenotypic features that distinguish bilateral isolated cryptophthalmos from other forms and discuss its relatively favorable prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13816810500374557DOI Listing
December 2005