Publications by authors named "Julie Richer"

27 Publications

  • Page 1 of 1

A Novel Recurrent Genetic Variant Is Associated With a Dysplasia-Associated Arterial Disease Exhibiting Dissections and Fibromuscular Dysplasia.

Arterioscler Thromb Vasc Biol 2020 11 17;40(11):2686-2699. Epub 2020 Sep 17.

Division of Cardiovascular Medicine, Department of Internal Medicine (H.L.H., Y.W., M.-L.Y., K.L.H., J.L., A.E.K., S.K.G.), University of Michigan Medical School, Ann Arbor.

Objective: While rare variants in the gene have been associated with classical Ehlers-Danlos syndrome and rarely with arterial dissections, recurrent variants in underlying a systemic arteriopathy have not been described. Monogenic forms of multifocal fibromuscular dysplasia (mFMD) have not been previously defined. Approach and Results: We studied 4 independent probands with the pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. Arterial medial fibroplasia and smooth muscle cell disorganization were confirmed histologically. The c.1540G>A variant is predicted to be pathogenic in silico and absent in gnomAD. The c.1540G>A variant is on a shared 160.1 kb haplotype with 0.4% frequency in Europeans. Furthermore, exome sequencing data from a cohort of 264 individuals with mFMD were examined for variants. In this mFMD cohort, c.1540G>A and 6 additional relatively rare variants predicted to be deleterious in silico were identified and were associated with arterial dissections (=0.005).

Conclusions: c.1540G>A is the first recurring variant recognized to be associated with arterial dissections and mFMD. This variant presents with a phenotype reminiscent of vascular Ehlers-Danlos syndrome. A shared haplotype among probands supports the existence of a common founder. Relatively rare genetic variants predicted to be deleterious by in silico analysis were identified in ≈2.7% of mFMD cases, and as they were enriched in patients with arterial dissections, may act as disease modifiers. Molecular testing for should be considered in patients with a phenotype overlapping with vascular Ehlers-Danlos syndrome and mFMD.
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http://dx.doi.org/10.1161/ATVBAHA.119.313885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953329PMC
November 2020

Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature.

J Inherit Metab Dis 2020 11 3;43(6):1321-1332. Epub 2020 Aug 3.

Research Center, CHU Sainte Justine, University of Montreal, Montreal, Quebec, Canada.

We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants in PIGQ.
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http://dx.doi.org/10.1002/jimd.12278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689772PMC
November 2020

The Responsibility to Recontact Research Participants after Reinterpretation of Genetic and Genomic Research Results.

Am J Hum Genet 2019 04;104(4):578-595

Social Issues Committee, American Society of Human Genetics, Rockville, MD 20852, USA; Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.

The evidence base supporting genetic and genomic sequence-variant interpretations is continuously evolving. An inherent consequence is that a variant's clinical significance might be reinterpreted over time as new evidence emerges regarding its pathogenicity or lack thereof. This raises ethical, legal, and financial issues as to whether there is a responsibility to recontact research participants to provide updates on reinterpretations of variants after the initial analysis. There has been discussion concerning the extent of this obligation in the context of both research and clinical care. Although clinical recommendations have begun to emerge, guidance is lacking on the responsibilities of researchers to inform participants of reinterpreted results. To respond, an American Society of Human Genetics (ASHG) workgroup developed this position statement, which was approved by the ASHG Board in November 2018. The workgroup included representatives from the National Society of Genetic Counselors, the Canadian College of Medical Genetics, and the Canadian Association of Genetic Counsellors. The final statement includes twelve position statements that were endorsed or supported by the following organizations: Genetic Alliance, European Society of Human Genetics, Canadian Association of Genetic Counsellors, American Association of Anthropological Genetics, Executive Committee of the American Association of Physical Anthropologists, Canadian College of Medical Genetics, Human Genetics Society of Australasia, and National Society of Genetic Counselors.
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http://dx.doi.org/10.1016/j.ajhg.2019.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451731PMC
April 2019

Valproic acid as a monotherapy in drug-resistant methyl-CpG-binding protein 2 gene (MECP2) duplication-related epilepsy.

Epilepsy Behav Case Rep 2018 9;10:133-136. Epub 2018 Oct 9.

Department of Pediatric Neurology, Children's Hospital of Eastern Ontario (CHEO), 401 Smyth Road, Ottawa, ON K1H 8L1, Canada.

Duplication of the methyl-CpG-binding protein 2 gene (MECP2) is a rare condition that results in epilepsy in half of the cases. Although this condition has been well characterized in the literature, there is a lack of research on MECP2 duplication-related epilepsy and its management. We present the case of an eleven-year old male with MECP2 duplication and epilepsy, who was resistant to polytherapy. The patient responded well to valproic acid (VPA) initially and upon re-challenge. This case report provides evidence for the use of VPA as an initial monotherapy for treatment of drug-resistant MECP2 duplication-related epilepsy.
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http://dx.doi.org/10.1016/j.ebcr.2018.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222037PMC
October 2018

Worster-Drought Syndrome Associated With Mutations.

Child Neurol Open 2018 2;5:2329048X18791083. Epub 2018 Aug 2.

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

Worster-Drought syndrome is a congenital, pseudobulbar paresis. There is no identified molecular etiology despite familial cases reported. The authors report a boy who was diagnosed with Worster-Drought syndrome due to longstanding drooling, dysphagia, and impaired tongue movement. Magnetic resonance imaging of the brain was unrevealing. At 14 years old, he remains aphonic with normal facial and extraocular movements. Nonsense mutations in the gene, p.Glu366X and p.Lys393X, were found. Results from neuropsychological testing at 14 years old were consistent with a diagnosis of intellectual disability and revealed nonverbal reasoning skills at a 5-year-old level with relative sparing of his receptive vocabulary and visual attention. Compared to prior testing at 9 years old, his receptive language improved from a 6-year-old to an 8.5-year-old level. The authors report mutations associated with Worster-Drought syndrome. This highlights that despite severe and persistent aphonia, receptive language improvements can be observed within the context of intellectual disability.
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http://dx.doi.org/10.1177/2329048X18791083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077897PMC
August 2018

Novel pathogenic variants in five families with arterial aneurysm and dissection: further delineation of the phenotype.

J Med Genet 2019 04 2;56(4):220-227. Epub 2018 Jul 2.

Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

Background: Missense variants in , encoding a key transcriptional regulator of transforming growth factor beta signalling, were recently reported to cause arterial aneurysmal disease.

Objectives: The aims of the study were to identify the genetic disease cause in families with aortic/arterial aneurysmal disease and to further define genotype-phenotype correlations.

Methods And Results: Using gene panel sequencing, we identified a nonsense variant and four missense variants, all affecting highly conserved amino acids in the MH2 domain. The premature stop codon (c.612dup; p.(Asn205*)) was identified in a marfanoid patient with aortic root dilatation and in his affected father. A p.(Asn318Lys) missense variant was found in a Marfan syndrome (MFS)-like case who presented with aortic root aneurysm and in her affected daughter with marfanoid features and mild aortic dilatation. In a man clinically diagnosed with Loeys-Dietz syndrome (LDS) that presents with aortic root dilatation and marked tortuosity of the neck vessels, another missense variant, p.(Ser397Tyr), was identified. This variant was also found in his affected daughter with hypertelorism and arterial tortuosity, as well as his affected mother. The third missense variant, p.(Asn361Thr), was discovered in a man presenting with coronary artery dissection. Variant genotyping in three unaffected family members confirmed its absence. The last missense variant, p.(Ser467Leu), was identified in a man with significant cardiovascular and connective tissue involvement.

Conclusion: Taken together, our data suggest that heterozygous loss-of-function variants can cause a wide spectrum of autosomal dominant aortic and arterial aneurysmal disease, combined with connective tissue findings reminiscent of MFS and LDS.
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http://dx.doi.org/10.1136/jmedgenet-2018-105304DOI Listing
April 2019

Secondary findings from next-generation sequencing: what does actionable in childhood really mean?

Genet Med 2019 01 6;21(1):124-132. Epub 2018 Jun 6.

Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada.

Purpose: We aimed to assess the definition of actionability of secondary findings in childhood, using a screening framework.

Methods: For 31 disorders on the American College of Medical Genetics and Genomics SF v.2.0 list, World Health Organization screening criteria were applied to assess actionability in childhood.

Results: The age of onset was variable. We categorized disorders based on the proportion of cases that presented in childhood: rare (n = 6), fewer than half the cases (n = 9), the majority of cases (n = 12), or unclear (n = 4). The age at initiation of intervention was based on the youngest age of onset reported, not evidence of the benefit of early intervention. For 15 disorders, guidelines were supported by a moderate quality of evidence for at least one recommendation. Only tuberous sclerosis complex had recommendations based on high-quality evidence. All others were based on evidence of low or very low quality.

Conclusion: We propose that actionability in childhood should be based on the proportion of cases that manifest in childhood and the quality of the evidence supporting intervention recommendations. Ideally, disclosure in childhood would be limited to disorders for which a majority of cases present in childhood and for which interventions are supported by evidence of at least moderate quality (i.e., multiple endocrine neoplasia type 2, retinoblastoma, tuberous sclerosis complex, Marfan syndrome, and Wilson's disease).
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http://dx.doi.org/10.1038/s41436-018-0034-4DOI Listing
January 2019

A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3.

Hum Mutat 2018 05 6;39(5):621-634. Epub 2018 Mar 6.

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

The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.
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http://dx.doi.org/10.1002/humu.23407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947146PMC
May 2018

Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations.

Genet Med 2018 10 4;20(10):1206-1215. Epub 2018 Jan 4.

Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, USA, Texas.

Purpose: Smooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle-dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management.

Methods: Medical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed.

Results: All patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes.

Conclusion: Based on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications.
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http://dx.doi.org/10.1038/gim.2017.245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034999PMC
October 2018

Broad spectrum of neuropsychiatric phenotypes associated with white matter disease in PTEN hamartoma tumor syndrome.

Am J Med Genet B Neuropsychiatr Genet 2018 Jan 20;177(1):101-109. Epub 2017 Nov 20.

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

White matter lesions have been described in patients with PTEN hamartoma tumor syndrome (PHTS). How these lesions correlate with the neurocognitive features associated with PTEN mutations, such as autism spectrum disorder (ASD) or developmental delay, has not been well established. We report nine patients with PTEN mutations and white matter changes on brain magnetic resonance imaging (MRI), eight of whom were referred for reasons other than developmental delay or ASD. Their clinical presentations ranged from asymptomatic macrocephaly with normal development/intellect, to obsessive compulsive disorder, and debilitating neurological disease. To our knowledge, this report constitutes the first detailed description of PTEN-related white matter changes in adult patients and in children with normal development and intelligence. We present a detailed assessment of the neuropsychological phenotype of our patients and discuss the relationship between the wide array of neuropsychiatric features and observed white matter findings in the context of these individuals.
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http://dx.doi.org/10.1002/ajmg.b.32610DOI Listing
January 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.

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

Benchmarking outcomes in the Neonatal Intensive Care Unit: Cytogenetic and molecular diagnostic rates in a retrospective cohort.

Am J Med Genet A 2017 Jul 9;173(7):1839-1847. Epub 2017 May 9.

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

Genetic disease and congenital anomalies continue to be a leading cause of neonate mortality and morbidity. A genetic diagnosis in the neonatal intensive care unit (NICU) can be a challenge given the associated genetic heterogeneity and early stage of a disease. We set out to evaluate the outcomes of Medical Genetics consultation in the NICU in terms of cytogenetic and molecular diagnostic rates and impact on management. We retrospectively reviewed 132 charts from patients admitted to the NICU who received a Medical Genetics diagnostic evaluation over a 2 year period. Of the 132 patients reviewed, 26% (34/132) received a cytogenetic or molecular diagnosis based on the Medical Genetics diagnostic evaluation; only 10% (13/132) received a diagnosis during their admission. The additional 16% (21 patients) received their diagnosis following NICU discharge, but based on a genetic test initiated during hospital-stay. Mean time from NICU admission to confirmed diagnosis was 24 days. For those who received a genetic diagnosis, the information was considered beneficial for clinical management in all, and a direct change to medical management occurred for 12% (4/32). For those non-diagnosed infants seen in out-patient follow-up clinic, diagnoses were made in 8% (3/37). The diagnoses made post-discharge from the NICU comprised a greater number of Mendelian disorders and represent an opportunity to improve genetic care. The adoption of diagnostic tools, such as exome sequencing, used in parallel with traditional approaches will improve rate of diagnoses and will have a significant impact, in particular when the differential diagnosis is broad.
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http://dx.doi.org/10.1002/ajmg.a.38250DOI Listing
July 2017

Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections.

Genet Med 2017 04 15;19(4):386-395. Epub 2016 Sep 15.

Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

Purpose: Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families.

Methods: We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed.

Results: We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-β signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture.

Conclusion: In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-β signaling.Genet Med 19 4, 386-395.
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http://dx.doi.org/10.1038/gim.2016.126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207316PMC
April 2017

Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit.

CMAJ 2016 Aug 30;188(11):E254-E260. Epub 2016 May 30.

Department of Genetics (Daoud, Luco, Beaulieu, Jarinova, Carson, Nikkel, Graham, Richer, Armour, Boycott, Dyment) and Department of Pediatrics (Bulman, Chakraborty, Geraghty, Lines, Lacaze-Masmonteil), Children's Hospital of Eastern Ontario, Ottawa, Ont.; McGill University (Li, Bareke, Majewski) and Genome Quebec Innovation Centre (Li, Bareke, Majewski), Montréal, Que.

Background: Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive consultations and traditional genetic or metabolic investigations are costly and often fail to arrive at a final diagnosis when no recognizable syndrome is suspected. For this pilot project, we assessed the feasibility of next-generation sequencing as a tool to improve the diagnosis of rare diseases in newborns in the NICU.

Methods: We retrospectively identified and prospectively recruited newborns and infants admitted to the NICU of the Children's Hospital of Eastern Ontario and the Ottawa Hospital, General Campus, who had been referred to the medical genetics or metabolics inpatient consult service and had features suggesting an underlying genetic or metabolic condition. DNA from the newborns and parents was enriched for a panel of clinically relevant genes and sequenced on a MiSeq sequencing platform (Illumina Inc.). The data were interpreted with a standard informatics pipeline and reported to care providers, who assessed the importance of genotype-phenotype correlations.

Results: Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myopathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys-Drash syndrome.

Interpretation: This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU.
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http://dx.doi.org/10.1503/cmaj.150823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978597PMC
August 2016

Screening Children for Familial Aortopathies: Tread With Caution.

Can J Cardiol 2016 Jan 22;32(1):60-5. Epub 2015 Oct 22.

Medical Genetics, Department of Pediatrics, and Research Center, CHU Sainte-Justine; and Department of Pediatrics, Université de Montréal; and Department of Medicine, Montreal Heart Institute, Montreal, Quebec, Canada.

The knowledge surrounding the genetic etiologies of familial aortopathies and familial thoracic aortic aneurysms and dissections has greatly expanded over the past few years. However, despite these advances, the underlying molecular etiology remains unidentified in most families with nonsyndromic familial aortopathies, and in a subset of families with syndromic aortopathies. In these families we cannot offer a genetic test to establish which family members are at risk. Although the general consensus has been to clinically follow all at-risk family members on the basis of family history, it remains unclear at the age at which to initiate clinical surveillance and the frequency which to screen asymptomatic relatives, whether or not a genetic etiology has been established in the family. These questions are particularly troublesome in a pediatric context where the risks of screening are potentially higher and the likelihood that such screening will provide immediate benefits is often lower than in adults. In this report we aim to: (1) provide clinicians with a framework within which to evaluate risks and benefits of screening asymptomatic pediatric patients for a family history of thoracic aortic aneurysms and dissections; and (2) provide a potential approach for patients (a) in whose family a disease-causing mutation has been identified, (b) patients in whose family the proband is syndromic, but does not have an identified disease-causing mutation, and (c) patients in whose family the proband is nonsyndromic and does not have an identified disease-causing mutation.
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http://dx.doi.org/10.1016/j.cjca.2015.10.005DOI Listing
January 2016

Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update.

Hum Mutat 2016 Feb 19;37(2):148-54. Epub 2015 Nov 19.

Department of Genetics, Sacramento Medical Center, Sacramento, California.

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).
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http://dx.doi.org/10.1002/humu.22924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512564PMC
February 2016

Homozygous mutation in the eukaryotic translation initiation factor 2alpha phosphatase gene, PPP1R15B, is associated with severe microcephaly, short stature and intellectual disability.

Hum Mol Genet 2015 Nov 24;24(22):6293-300. Epub 2015 Aug 24.

Children's Hospital of Eastern Ontario Research Institute, Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1

Protein translation is an essential cellular process initiated by the association of a methionyl-tRNA with the translation initiation factor eIF2. The Met-tRNA/eIF2 complex then associates with the small ribosomal subunit, other translation factors and mRNA, which together comprise the translational initiation complex. This process is regulated by the phosphorylation status of the α subunit of eIF2 (eIF2α); phosphorylated eIF2α attenuates protein translation. Here, we report a consanguineous family with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings. Whole-exome sequencing identified a homozygous missense mutation, c.1972G>A; p.Arg658Cys, in protein phosphatase 1, regulatory subunit 15b (PPP1R15B), a protein which functions with the PPP1C phosphatase to maintain dephosphorylated eIF2α in unstressed cells. The p.R658C PPP1R15B mutation is located within the PPP1C binding site. We show that patient cells have greatly diminished levels of PPP1R15B-PPP1C interaction, which results in increased eIF2α phosphorylation and resistance to cellular stress. Finally, we find that patient cells have elevated levels of PPP1R15B mRNA and protein, suggesting activation of a compensatory program aimed at restoring cellular homeostasis which is ineffective due to PPP1R15B alteration. PPP1R15B now joins the expanding list of translation-associated proteins which when mutated cause rare genetic diseases.
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http://dx.doi.org/10.1093/hmg/ddv337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614701PMC
November 2015

The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists.

J Med Genet 2015 Jul 7;52(7):431-7. Epub 2015 May 7.

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

Purpose And Scope: The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals.

Methods Of Statement Development: Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada.

Results And Conclusions: Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely re-evaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally.
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http://dx.doi.org/10.1136/jmedgenet-2015-103144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501167PMC
July 2015

Resolution of refractory hypotension and anuria in a premature newborn with loss-of-function of ACE.

Am J Med Genet A 2015 Jul 21;167(7):1654-8. Epub 2015 Apr 21.

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

We present the investigation and management of a premature, hypotensive neonate born after a pregnancy complicated by anhydramnios to highlight the impact of early and informed management for rare kidney disease. Vasopressin was used to successfully treat refractory hypotension and anuria in the neonate born at 27 weeks of gestation. Next generation sequencing of a targeted panel of genes was then performed in the neonate and parents. Subsequently, two compound heterozygous deletions leading to frameshift mutations were identified in the angiotensin 1-converting enzyme gene ACE; exon 5:c.820_821delAG (p.Arg274Glyfs*117) and exon24: c.3521delG (p.Gly1174Alafs*12), consistent with a diagnosis of renal tubular dysgenesis. In light of the molecular diagnosis, identification, and treatment of associated low aldosterone level resulted in further improvement in renal function and only mild residual chronic renal failure is present at 14 months of age. Truncating alterations in ACE most often result in fetal demise during gestation or in the first days of life and typically as a result of the Potter sequence. The premature delivery, and serendipitous early treatment with vasopressin, and then later fludrocortisone, resulted in an optimal outcome in an otherwise lethal condition.
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http://dx.doi.org/10.1002/ajmg.a.37067DOI Listing
July 2015

De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.

Hum Mutat 2015 Apr 17;36(4):454-62. Epub 2015 Mar 17.

Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, Medical School, University of Zaragoza, CIBERER-GCV and ISS-Aragon, Zaragoza, Spain.

Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ∼ 1%-2% of CdLS-like phenotypes.
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http://dx.doi.org/10.1002/humu.22761DOI Listing
April 2015

Expanding the clinical spectrum of ocular anomalies in Noonan syndrome: Axenfeld-anomaly in a child with PTPN11 mutation.

Am J Med Genet A 2015 Feb 25;167A(2):403-6. Epub 2014 Nov 25.

The Hospital for Sick Children, Department of Pediatrics, Division of Clinical and Metabolic Genetics, Toronto, Ontario, Canada; Kingston General Hospital, Department of Pediatrics, Division of Medical Genetics, Kingston, Ontario, Canada.

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.
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http://dx.doi.org/10.1002/ajmg.a.36841DOI Listing
February 2015

Returning incidental findings from genetic research to children: views of parents of children affected by rare diseases.

J Med Ethics 2014 Oct 19;40(10):691-6. Epub 2013 Dec 19.

Centre of Genomics and Policy, McGill University, Montreal, Quebec, Canada.

Purpose: To explore parental perceptions and experiences regarding the return of genomic incidental research findings in children with rare diseases.

Methods: Parents of children affected by various rare diseases were invited to participate in focus groups or individual telephone interviews in Montreal and Ottawa. Fifteen participants were interviewed and transcriptions were analysed using thematic analysis.

Results: Four emergent themes underscored parental enthusiasm for receiving incidental findings concerning their child's health: (1) right to information; (2) perceived benefits and risks; (3) communication practicalities: who, when, and how; and (4) service needs to promote the communication of incidental findings. Parents believed they should be made aware of all results pertaining to their child's health status, and that they are responsible for transmitting this information to their child, irrespective of disease severity. Despite potential negative consequences, respondents generally perceived a favourable risk-benefit ratio in receiving all incidental findings.

Conclusions: Understanding how parents assess the risks and benefits of returning incidental findings is essential to genomic research applications in paediatric medicine. The authors believe the study findings will contribute to establishing future best practices, although further research is needed to evaluate the impact of parental decisions on themselves and their child.
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http://dx.doi.org/10.1136/medethics-2013-101648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173986PMC
October 2014

Research use of leftover newborn bloodspots: attitudes of Canadian geneticists regarding storage and informed consent requirements.

Genet Med 2011 Apr;13(4):305-13

Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada.

Purpose: Leftover newborn spots can provide a powerful research tool as a population-wide DNA bank. Some provinces/states store them for more than 20 years; however, parents are usually not informed of the retention of leftover newborn spots. To examine the opinions of Canadian geneticists regarding permission for leftover newborn spots storage for research purposes and the associated risks, a web-based survey was distributed to all members of the Canadian College of Medical Geneticists with a valid e-mail address (n = 209) and completed by 78 respondents (37%).

Results: The majority of respondents (73%) favored opt-out notification for retention of samples that would be held for longer than 2 years. For research on multifactorial conditions using leftover newborn spots originally banked without parental permission, geneticists favored different types of permission depending on the level of identifiable information attached to samples. Thirty-eight percent were concerned that information pamphlets that state that leftover newborn spots will be stored and may be "a source of DNA for research" would lead to a decreased participation in newborn screening. Twenty-eight percent believed that group stigma or family anxiety was likely to result from using nonidentified leftover newborn spots to study multifactorial conditions.

Conclusion: The concerns of this knowledgeable cohort supports the critical importance of public engagement about both the potential risks and societal benefits associated with the use of leftover newborn spots in research as policy for leftover newborn spots is developed.
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http://dx.doi.org/10.1097/GIM.0b013e3181f69da0DOI Listing
April 2011

Distal trisomy 10q syndrome: phenotypic features in a child with inverted duplicated 10q25.1-q26.3.

Clin Dysmorphol 2010 Jul;19(3):140-145

Division of Developmental Paediatrics, Bloorview Kids Rehab, Toronto Eastern Ontario Regional Genetics Program, Children's Hospital of Eastern Ontario, Ottawa, Ontario Maritime Medical Genetics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.

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http://dx.doi.org/10.1097/MCD.0b013e3283377915DOI Listing
July 2010
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