Publications by authors named "Sarah M Nikkel"

35 Publications

Etiologies and outcomes of prenatally diagnosed hyperechogenic kidneys.

Prenat Diagn 2020 Dec 18. Epub 2020 Dec 18.

Provincial Medical Genetics Program, BC Women's Hospital, Vancouver, British Columbia, Canada.

Objectives: To determine etiologies and outcomes of fetal hyperechogenic kidneys (HEK).

Methods: We conducted a retrospective chart review of HEK in British Columbia (January 2013-December 2019) and literature review.

Results: We identified 20 cases of HEK without other anomalies (isolated) in our provincial cohort, one was lost to follow-up. Eight had testable genetic etiologies (autosomal dominant polycystic kidney disease [ADPKD], autosomal recessive polycystic kidney disease [ARPKD], Bardet-Biedl syndrome [BBS], and HNF1B-related disorder). The remaining seven did not have an identifiable genetic etiology. Of cases without a genetic etiology with postnatal follow-up (n = 6) there were no abnormalities of blood pressure, creatinine/estimated glomerular filtration rate or urinalysis identified with follow-up from 2-71 months. We report 11 cases with extrarenal anomalies (nonisolated), with outcomes and etiologies. We identified 224 reported cases of isolated HEK in the literature. A potentially testable genetic etiology was found in 128/224 (57.1%). The neonatal death rate in those with testable etiologies was 17/128 (13.3%) compared to 2/96 (2.1%) when testable etiologies were excluded.

Conclusions: Genetic etiologies (ARPKD, ADPKD, BBS, HNF1B-related disorder, Beckwith-Wiedemann syndrome, tubular dysgenesis, familial nephroblastoma, and cytogenetic abnormalities) account for approximately half of prenatally isolated HEK; once excluded there are few neonatal deaths and short-term renal outcomes may be normal. There remains a paucity of knowledge about long-term renal outcomes.
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http://dx.doi.org/10.1002/pd.5883DOI Listing
December 2020

Microarray results as an indicator of sexual abuse.

Paediatr Child Health 2020 Apr 10;25(3):134-135. Epub 2019 Apr 10.

Division of Child and Youth Protection, Department of Pediatrics, University of Ottawa, Ottawa, Ontario.

This case report illustrates the unexpected identification of intrafamilial sexual abuse of a young mother through genetic testing of her child. The child's genome was found to have a relatively common chromosomal condition with congruent clinical manifestations, but the microarray also suggested a close biological relationship between the parents because of a high degree of homozygosity. This prompted a child protection investigation as the mother had been a minor at the time of conception, and intrafamilial sexual abuse was confirmed. Both the intended and unintended results of microarray should be considered with respect to the health and social context of the child and their biological parents. This becomes particularly important for young mothers and raises protection concerns when significant amounts of homozygosity (consanguinity) are detected.
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http://dx.doi.org/10.1093/pch/pxz034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147699PMC
April 2020

RAPIDOMICS: rapid genome-wide sequencing in a neonatal intensive care unit-successes and challenges.

Eur J Pediatr 2019 Aug 7;178(8):1207-1218. Epub 2019 Jun 7.

Division of Neonatology, Department of Paediatrics, University of British Columbia, Vancouver, Canada.

Genetic disorders are one of the leading causes of infant mortality and are frequent in neonatal intensive care units (NICUs). Rapid genome-wide sequencing (GWS; whole genome or exome sequencing (ES)), due to its diagnostic capabilities and immediate impacts on medical management, is becoming an appealing testing option in the NICU setting. RAPIDOMICS was a trio-based rapid ES pilot study of 25 babies with suspected genetic disorders in the BC Women's Hospital NICU. ES and bioinformatic analysis were performed after careful patient ascertainment. Trio analysis was performed using an in-house pipeline reporting variants in known disease-causing genes. Variants interpreted by the research team as definitely or possibly causal of the infant's phenotype were Sanger validated in a clinical laboratory. The average time to preliminary diagnosis was 7.2 days. Sanger validation was pursued in 15 patients for 13 autosomal dominant and 2 autosomal recessive disorders, with an overall diagnostic rate (partial or complete) of 60%.Conclusion: In total, 72% of patients enrolled had a genomic diagnosis achieved through ES, multi-gene panel testing or chromosomal microarray analysis. Among these, there was an 83% rate of significant and immediate impact on medical decision-making directly related to new knowledge of the diagnosis. Health service implementation challenges and successes are discussed. What is Known: • Rapid genome-wide sequencing in the neonatal intensive care setting has a greater diagnostic hit rate and impact on medical management than conventional genetic testing. However, the impact of consultation with genetics and patient ascertainment requires further investigation. What is New: • This study demonstrates the importance of genetic consultation and careful patient selection prior to pursuing exome sequencing (ES). • In total, 15/25 (60%) patients achieved a diagnosis through ES and 18/25 (72%) through ES, multi-gene panel testing or chromosomal microarray analysis with 83% of those having immediate effects on medical management.
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http://dx.doi.org/10.1007/s00431-019-03399-4DOI Listing
August 2019

Diagnostic clarity of exome sequencing following negative comprehensive panel testing in the neonatal intensive care unit.

Am J Med Genet A 2018 07;176(7):1688-1691

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

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http://dx.doi.org/10.1002/ajmg.a.38838DOI Listing
July 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

A de novo mutation in RPL10 causes a rare X-linked ribosomopathy characterized by syndromic intellectual disability and epilepsy: A new case and review of the literature.

Eur J Med Genet 2018 Feb 21;61(2):89-93. Epub 2017 Oct 21.

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

Intellectual disability (ID) affects 1-2% of the general population and up to 50% of those with ID are estimated to have an underlying genetic cause. Next-generation sequencing provides an efficient means to identify the molecular causes of monogenic forms of ID. Here we present an 18 year old male with severe ID, absent speech, microcephaly, ataxia, dysmorphic facial features, and a refractory, early-onset seizure disorder. Exome sequencing revealed a rare de novo mutation in the X-linked gene RPL10 (c.232A > G, p.K78E). Previous reports of inherited mutations in RPL10 have suggested a role for the gene in neurodevelopment and the individual reported shows marked similarities to three members of a family with the same mutation reported in the literature. The p.K78E substitution appears to be associated with severe microcephaly, seizures, hearing loss, growth retardation, cardiac defects, and dysmorphic facial features. This is the first instance that a de novo mutation in RPL10 has been reported.
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http://dx.doi.org/10.1016/j.ejmg.2017.10.011DOI Listing
February 2018

Skeletal Dysplasias: What Every Bone Health Clinician Needs to Know.

Authors:
Sarah M Nikkel

Curr Osteoporos Rep 2017 10;15(5):419-424

Provinical Medical Genetics Program, BC Women's Hospital and Health Centre, University of British Columbia, 4500 Oak Street, Vancouver, BC, V6H 3N1, Canada.

Purpose Of Review: This review highlights how skeletal dysplasias are diagnosed and how our understanding of some of these conditions has now translated to treatment options.

Recent Findings: The use of multigene panels, using next-generation sequence technology, has improved our ability to quickly identify the genetic etiology, which can impact management. There are successes with the use of growth hormone in individuals with SHOX deficiencies, asfotase alfa in hypophosphatasia, and some promising data for c-type natriuretic peptide for those with achondroplasia. One needs to consider that a patient with short stature has a skeletal dysplasia as options for management may be available.
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http://dx.doi.org/10.1007/s11914-017-0392-xDOI Listing
October 2017

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

Autosomal dominant cutis laxa with progeroid features due to a novel, de novo mutation in ALDH18A1.

J Hum Genet 2017 Jun 23;62(6):661-663. Epub 2017 Feb 23.

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

De novo dominant mutations in the aldehyde dehydrogenase 18 family member A1 (ALDH18A1) gene have recently been shown to cause autosomal dominant cutis laxa with progeroid features (MIM 616603). To date, all de novo dominant mutations have been found in a single highly conserved amino acid residue at position p.Arg138. We report an 8-year-old male with a clinical diagnosis of autosomal dominant cutis laxa (ADCL) with progeroid features and a novel de novo missense mutation in ALDH18A1 (NM_002860.3: c.377G>A (p.Arg126His)). This is the first report of an individual with ALDH18A1-ADCL due to a substitution at a residue other than p.Arg138. Knowledge of the complete spectrum of dominant-acting mutations that cause this rare syndrome will have implications for molecular diagnosis and genetic counselling of these families.
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http://dx.doi.org/10.1038/jhg.2017.18DOI Listing
June 2017

The defining DNA methylation signature of Floating-Harbor Syndrome.

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

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

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

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

Fetal segmental spinal dysgenesis and unusual segmental agenesis of the anterior spinal artery.

Childs Nerv Syst 2016 Aug 11;32(8):1537-41. Epub 2016 Mar 11.

Department of Medical Imaging, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, K1H 8L1, Canada.

Segmental spinal dysgenesis (SSD) is a rare congenital spinal abnormality characterized by segmental dysgenesis or agenesis of the thoracolumbar or lumbar spine, congenital kyphosis, and abnormal configuration of the underlying spinal cord. A unique feature of SSD is that the vertebrae are present above and below the defect, and there is often a lower cord segment in the caudal spinal canal. We report a fetal MRI case of SSD with postmortem and neuropathological correlations. Our report confirms already published findings including the presence of a neurenteric cyst but is the first to document anterior spinal artery segmental agenesis in SSD.
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http://dx.doi.org/10.1007/s00381-016-3054-xDOI Listing
August 2016

Relationships between Head Circumference, Brain Volume and Cognition in Children with Prenatal Alcohol Exposure.

PLoS One 2016 29;11(2):e0150370. Epub 2016 Feb 29.

Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.

Head circumference is used together with other measures as a proxy for central nervous system damage in the diagnosis of fetal alcohol spectrum disorders, yet the relationship between head circumference and brain volume has not been investigated in this population. The objective of this study is to characterize the relationship between head circumference, brain volume and cognitive performance in a large sample of children with prenatal alcohol exposure (n = 144) and healthy controls (n = 145), aged 5-19 years. All participants underwent magnetic resonance imaging to yield brain volumes and head circumference, normalized to control for age and sex. Mean head circumference, brain volume, and cognitive scores were significantly reduced in the prenatal alcohol exposure group relative to controls, albeit with considerable overlap between groups. Males with prenatal alcohol exposure had reductions in all three measures, whereas females with prenatal alcohol exposure had reduced brain volumes and cognitive scores, but no difference in head circumference relative to controls. Microcephaly (defined here as head circumference ≤ 3rd percentile) occurred more often in prenatal alcohol exposed participants than controls, but 90% of the exposed sample had head circumferences above this clinical cutoff indicating that head circumference is not a sensitive marker of prenatal alcohol exposure. Normalized head circumference and brain volume were positively correlated in both groups, and subjects with very low head circumference typically had below-average brain volumes. Conversely, over half of the subjects with very low brain volumes had normal head circumferences, which may stem from differential effects of alcohol on the skeletal and nervous systems. There were no significant correlations between head circumference and any cognitive score. These findings confirm group-level reductions in head circumference and increased rates of microcephaly in children with prenatal alcohol exposure, but raise concerns about the predictive value of this metric at an individual-subject level.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150370PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771159PMC
July 2016

Two novel disease-causing variants in BMPR1B are associated with brachydactyly type A1.

Eur J Hum Genet 2015 Dec 11;23(12):1640-5. Epub 2015 Mar 11.

Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.

Brachydactyly type A1 is an autosomal dominant disorder primarily characterized by hypoplasia/aplasia of the middle phalanges of digits 2-5. Human and mouse genetic perturbations in the BMP-SMAD signaling pathway have been associated with many brachymesophalangies, including BDA1, as causative mutations in IHH and GDF5 have been previously identified. GDF5 interacts directly as the preferred ligand for the BMP type-1 receptor BMPR1B and is important for both chondrogenesis and digit formation. We report pathogenic variants in BMPR1B that are associated with complex BDA1. A c.975A>C (p.(Lys325Asn)) was identified in the first patient displaying absent middle phalanges and shortened distal phalanges of the toes in addition to the significant shortening of middle phalanges in digits 2, 3 and 5 of the hands. The second patient displayed a combination of brachydactyly and arachnodactyly. The sequencing of BMPR1B in this individual revealed a novel c.447-1G>A at a canonical acceptor splice site of exon 8, which is predicted to create a novel acceptor site, thus leading to a translational reading frameshift. Both mutations are most likely to act in a dominant-negative manner, similar to the effects observed in BMPR1B mutations that cause BDA2. These findings demonstrate that BMPR1B is another gene involved with the pathogenesis of BDA1 and illustrates the continuum of phenotypes between BDA1 and BDA2.
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http://dx.doi.org/10.1038/ejhg.2015.38DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795202PMC
December 2015

Meconium ileus in a Lebanese family secondary to mutations in the GUCY2C gene.

Eur J Hum Genet 2015 Jul 5;23(7):990-2. Epub 2014 Nov 5.

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

Meconium ileus is most often associated with mutations in the CFTR gene; however recently, mutations in GUCY2C in the Bedouin population have also been shown to result in this phenotype. This gene codes for an intestinal transmembrane receptor that generates cyclic GMP, which activates cystic fibrosis transmembrane receptor. We report a third family that supports the association of variants in the GUCY2C gene with meconium ileus (MI). A Lebanese kindred was studied and individuals affected with MI had either homozygous or compound heterozygous variants in GUCY2C. The earliest manifestation of the affected individuals was the presence of second trimester fetal echogenic bowel, thus resulting in the expansion of the differential diagnosis of this ultrasound finding.
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http://dx.doi.org/10.1038/ejhg.2014.236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463511PMC
July 2015

Growth and development in thanatophoric dysplasia - an update 25 years later.

Clin Case Rep 2013 Dec 15;1(2):75-8. Epub 2013 Nov 15.

Department of Pediatrics, University of Ottawa Ottawa, Ontario, Canada ; Department of Pediatrics, Children's Hospital of Eastern Ontario Ottawa, Ontario, Canada.

Key Clinical Message: Thanatophoric dysplasia is typically a neonatal lethal condition. However, for those rare individuals who do survive, there is the development of seizures, progression of craniocervical stenosis, ventilator dependence, and limitations in motor and cognitive abilities. Families must be made aware of these issues during the discussion of management plans.
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http://dx.doi.org/10.1002/ccr3.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184754PMC
December 2013

Noninvasive prenatal testing from cell-free DNA.

CMAJ 2014 Sep 7;186(12):934. Epub 2014 Apr 7.

Eastern Ontario Regional Genetics Program, Department of Genetics (Armour, Nikkel), Children's Hospital of Eastern Ontario; Children's Hospital of Eastern Ontario Research Institute (Armour), Ottawa, Ont.

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http://dx.doi.org/10.1503/cmaj.131551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150709PMC
September 2014

Working memory and visuospatial deficits correlate with oculomotor control in children with fetal alcohol spectrum disorder.

Behav Brain Res 2014 Apr 29;263:70-9. Epub 2014 Jan 29.

Centre for Neuroscience Studies, Queens University, Kingston, ON, Canada. Electronic address:

Previous studies have demonstrated that children with Fetal Alcohol Spectrum Disorder (FASD) exhibit deficits in measures of eye movement control that probe aspects of visuospatial processing and working memory. The goal of the present study was to examine, in a large cohort of children with FASD, prenatal alcohol exposure (PAE) but not FASD, and typically developing control children, the relationship between performance in eye movement tasks and standardized psychometric tests that assess visuospatial processing and working memory. Participants for this dataset were drawn from a large, multi-site investigation, and included children and adolescents aged 5-17 years diagnosed with an FASD (n=71), those with PAE but no clinical FASD diagnosis (n=20), and typically developing controls (n=111). Participants completed a neurobehavioral test battery and a series of saccadic eye movement tasks. The FASD group performed worse than controls on the psychometric and eye movement measures of working memory and visuospatial skills. Within the FASD group, digit recall, block recall, and animal sorting were negatively correlated with sequence errors on the memory-guided task, and arrows was negatively correlated with prosaccade endpoint error. There were no significant correlations in the control group. These data suggest that psychometric tests and eye movement control tasks may assess similar domains of cognitive function, and these assessment tools may be measuring overlapping brain regions damaged due to prenatal alcohol exposure. The results of this study demonstrate that eye movement control tasks directly relate to outcome measures obtained with psychometric tests and are able to assess multiple domains of cognition simultaneously, thereby allowing for an efficient and accurate assessment.
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http://dx.doi.org/10.1016/j.bbr.2014.01.024DOI Listing
April 2014

Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes.

Hum Mol Genet 2014 May 30;23(10):2752-68. Epub 2013 Dec 30.

The Centre for Applied Genomics.

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
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http://dx.doi.org/10.1093/hmg/ddt669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990173PMC
May 2014

Deficits in response inhibition correlate with oculomotor control in children with fetal alcohol spectrum disorder and prenatal alcohol exposure.

Behav Brain Res 2014 Feb 1;259:97-105. Epub 2013 Nov 1.

Centre for Neuroscience Studies, Queens University, Kingston, ON, Canada. Electronic address:

Children with fetal alcohol spectrum disorder (FASD) or prenatal alcohol exposure (PAE) frequently exhibit impairment on tasks measuring inhibition. The objective of this study was to determine if a performance-based relationship exists between psychometric tests and eye movement tasks in children with FASD. Participants for this dataset were aged 5-17 years and included those diagnosed with an FASD (n=72), those with PAE but no clinical FASD diagnosis (n=21), and typically developing controls (n=139). Participants completed a neurobehavioral test battery, which included the NEPSY-II subtests of auditory attention, response set, and inhibition. Each participant completed a series of saccadic eye movement tasks, which included the antisaccade and memory-guided tasks. Both the FASD and the PAE groups performed worse than controls on the subtest measures of attention and inhibition. Compared with controls, the FASD group made more errors on the antisaccade and memory-guided tasks. Among the combined FASD/PAE group, inhibition and switching errors were negatively correlated with direction errors on the antisaccade task but not on the memory-guided task. There were no significant correlations in the control group. These data suggests that response inhibition deficits in children with FASD/PAE are associated with difficulty controlling saccadic eye movements which may point to overlapping brain regions damaged by prenatal alcohol exposure. The results of this study demonstrate that eye movement control tasks directly relate to outcome measures obtained with psychometric tests that are used during FASD diagnosis, and may therefore help with early identification of children who would benefit from a multidisciplinary diagnostic assessment.
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http://dx.doi.org/10.1016/j.bbr.2013.10.040DOI Listing
February 2014

Hippocampal hypoplasia in Smith-Lemli-Opitz syndrome.

Pediatr Dev Pathol 2013 Jul-Aug;16(4):318-20. Epub 2013 May 20.

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http://dx.doi.org/10.2350/12-09-1252-LET.1DOI Listing
October 2013

The phenotype of Floating-Harbor syndrome: clinical characterization of 52 individuals with mutations in exon 34 of SRCAP.

Orphanet J Rare Dis 2013 Apr 27;8:63. Epub 2013 Apr 27.

Background: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome.

Methods And Results: Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations.

Conclusions: This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.
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http://dx.doi.org/10.1186/1750-1172-8-63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659005PMC
April 2013

Identification of novel mutations confirms PDE4D as a major gene causing acrodysostosis.

Hum Mutat 2013 Jan 9;34(1):97-102. Epub 2012 Nov 9.

Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.

Acrodysostosis is characterized by nasal hypoplasia, peripheral dysostosis, variable short stature, and intellectual impairment. Recently, mutations in PRKAR1A were reported in patients with acrodysostosis and hormone resistance. Subsequently, mutations in a phosphodiesterase gene (PDE4D) were identified in seven sporadic cases. We sequenced PDE4D in seven acrodysostosis patients from five families. Missense mutations were identified in all cases. Families showed de novo inheritance except one family with three affected children whose father was subsequently found to have subtle features of acrodysostosis. There were no recurrent mutations. Short stature and endocrine resistance are rare in this series; however, cognitive involvement and obesity were frequent. This last finding is relevant given PDE4D is insulin responsive and potentially involved in lipolysis. PDE4D encodes a cyclic AMP regulator and places PDE4D-related acrodysostosis within the same family of diseases as pseudohypoparathyroidism, pseudopseudohypoparathyroidism, PRKAR1A-related acrodysostosis and brachydactyly-mental retardation syndrome; all characterized by cognitive impairment and short distal extremities.
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http://dx.doi.org/10.1002/humu.22222DOI Listing
January 2013

Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog.

J Med Genet 2012 Jul;49(7):473-9

Medical Genetics Branch, National Human Genome Research Institute, NationalInstitutes of Health, Bethesda, MD, USA.

Background: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences.

Objective: To characterise genetic and clinical findings in individuals with SHH mutations.

Methods: Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases.

Results: This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype-phenotype correlations could be established regarding mutation location.

Conclusions: SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.
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http://dx.doi.org/10.1136/jmedgenet-2012-101008DOI Listing
July 2012

De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.

Nat Genet 2012 Jun 24;44(8):934-40. Epub 2012 Jun 24.

Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, Washington, USA.

Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features. We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism.
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http://dx.doi.org/10.1038/ng.2331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408813PMC
June 2012

Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome.

Am J Hum Genet 2012 Feb 19;90(2):308-13. Epub 2012 Jan 19.

Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.

Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS.
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http://dx.doi.org/10.1016/j.ajhg.2011.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276662PMC
February 2012

Mutations in GDF5 presenting as semidominant brachydactyly A1.

Hum Mutat 2010 Oct;31(10):1155-62

Department of Regenerative Medicine, Ottawa Hospital Research Institute, and University of Ottawa Centre for Neuromuscular Disease, Ottawa, ON, Canada.

Brachydactyly A1 (BDA1) is an autosomal dominant disorder characterized by shortness of all middle phalanges of the hands and toes, shortness of the proximal phalanges of the first digit, and short stature. Missense mutations in the Indian Hedgehog gene (IHH) are known to cause BDA1, and a second locus has been mapped to chromosome 5p. In a consanguineous French Canadian kindred with BDA1, both IHH and the 5p locus were excluded. Microsatellites flanking GDF5 on chromosome 20q were found to cosegregate with the disease. Sequencing of the GDF5 coding region revealed that a mildly affected individual in the family was heterozygous, and that all of the severely affected individuals were homozygous for a novel missense c.1195C>T mutation that predicts a p.Arg399Cys substitution at a highly conserved amino acid. Functional analysis demonstrated that although the p.Arg399Cys mutant is able to stimulate chondrogenesis, it is much less effective than wild-type GDF5. This data confirms genetic heterogeneity in BDA1, demonstrates that mutations upstream of IHH can result in BDA1, and shows that BDA1 can result from semidominant mutations in GDF5.
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http://dx.doi.org/10.1002/humu.21338DOI Listing
October 2010

Brachydactyly A-1 mutations restricted to the central region of the N-terminal active fragment of Indian Hedgehog.

Eur J Hum Genet 2009 Sep 11;17(9):1112-20. Epub 2009 Mar 11.

Ottawa Health Research Institute, Ottawa, Ontario, Canada.

Mutations in the gene Indian Hedgehog (IHH) that cause Brachydactyly A-1 (BDA1) have been restricted to a specific region of the N-terminal active fragment of Indian Hedgehog involving codons 95, 100, 131, and 154. We describe two novel mutations in codons 128 and 130, not previously implicated in BDA1. Furthermore, we identified an independent mutation at codon 131 and we also describe a New Zealand family, which carries the 'Farabee' founder mutation and haplotype. All of the BDA1 mutations occur in a restricted area of the N-terminal active fragment of the IHH and are in contrast to those mutations causing an autosomal recessive acrocapitofemoral dysplasia, whose mutations are located at the distal N- and C-terminal regions of IHH-N and are physically separated from the BDA1-causing mutations. The identification of multiple independent mutations in codons 95, 100, and now in 131, implicate a discrete function for this region of the protein. Finally, we present a clinical review of all reported and confirmed cases of BDA1, highlighting features of the disorder, which add to the spectrum of the IHH mutations.
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http://dx.doi.org/10.1038/ejhg.2009.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986602PMC
September 2009