Publications by authors named "Monica H Wojcik"

45 Publications

Mortality in the neonatal intensive care unit: improving the accuracy of death reporting.

J Perinatol 2021 Sep 28. Epub 2021 Sep 28.

Division of Newborn Medicine, Boston, MA, USA.

Objective: Death certificates commonly contain errors, which hinders understanding of infant mortality. We, therefore, undertook a quality improvement (QI) initiative to improve death reporting in our neonatal intensive care unit (NICU).

Study Design: After our baseline assessment (January 1, 2015 to June 30, 2017), we implemented our QI initiatives using Plan, Do, Study, Act (PDSA) tests of change. We prospectively reviewed death certificates (July 1, 2017 to December 31, 2019) to evaluate the impact of our interventions.

Results: The overall proportion of incorrect death certificates significantly decreased from 71 to 22% with special cause variation noted after the second PDSA cycle. The most common errors involved inaccurate or incomplete reporting of prematurity and errors in the sequence of events.

Conclusion: Through a series of PDSA cycles focused on formal provider education and ongoing review, we significantly reduced inaccurate death reporting. These interventions are generalizable across NICUs and important to improve public health reporting accuracy.
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http://dx.doi.org/10.1038/s41372-021-01214-3DOI Listing
September 2021

Neuroimaging in Kabuki syndrome and another KMT2D-related disorder.

Am J Med Genet A 2021 12 9;185(12):3770-3783. Epub 2021 Aug 9.

Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.

Recognition of distinct phenotypic features is an important component of genetic diagnosis. Although CHARGE syndrome, Kabuki syndrome, and a recently delineated KMT2D Ex 38/39 allelic disorder exhibit significant overlap, differences on neuroimaging may help distinguish these conditions and guide genetic testing and variant interpretation. We present an infant clinically diagnosed with CHARGE syndrome but subsequently found to have a de novo missense variant in exon 38 of KMT2D, the gene implicated in both Kabuki syndrome and a distinct KMT2D allelic disorder. We compare her brain and inner ear morphology to a retrospective cohort of 21 patients with classic Kabuki syndrome and to typical CHARGE syndrome findings described in the literature. Thirteen of the 21 Kabuki syndrome patients had temporal bone imaging (5/13 CT, 12/13 MRI) and/or brain MRI (12/13) which revealed findings distinct from both CHARGE syndrome and the KMT2D allelic disorder. Our findings further elucidate the spectrum of inner ear dysmorphology distinguishing Kabuki syndrome and the KMT2D allelic disorder from CHARGE syndrome, suggesting that these three disorders may be differentiated at least in part by their inner ear anomalies.
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http://dx.doi.org/10.1002/ajmg.a.62450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595668PMC
December 2021

The Unrecognized Mortality Burden of Genetic Disorders in Infancy.

Am J Public Health 2021 07;111(S2):S156-S162

Monica H. Wojcik and Pankaj B. Agrawal are with the Division of Newborn Medicine and Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA. Rachel Stadelmaier is with the Department of Pediatrics, Boston Children's Hospital and Harvard Medical School. Dominique Heinke is with the Center for Birth Defects Research and Prevention, Massachusetts Department of Public Health and Harvard T. H. Chan School of Public Health, Harvard University, Boston. Ingrid A. Holm and Wen-Hann Tan are with the Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School.

To determine how deaths of infants with genetic diagnoses are described in national mortality statistics. We present a retrospective cohort study of mortality data, obtained from the National Death Index (NDI), and clinical data for 517 infants born from 2011 to 2017 who died before 1 year of age in the United States. Although 115 of 517 deceased infants (22%) had a confirmed diagnosis of a genetic disorder, only 61 of 115 deaths (53%) were attributed to , codes representing congenital anomalies or genetic disorders (Q00-Q99) as the underlying cause of death because of inconsistencies in death reporting. Infants with genetic diagnoses whose underlying causes of death were coded as Q00-Q99 were more likely to have chromosomal disorders than monogenic conditions (43/61 [70%] vs 18/61 [30%];  < .001), which reflects the need for improved accounting for monogenic disorders in mortality statistics. Genetic disorders, although a leading cause of infant mortality, are not accurately captured by vital statistics. . Expanded access to genetic testing and further clarity in death reporting are needed to describe properly the contribution of genetic disorders to infant mortality.
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http://dx.doi.org/10.2105/AJPH.2021.306275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495634PMC
July 2021

Medical and surgical interventions and outcomes for infants with trisomy 18 (T18) or trisomy 13 (T13) at children's hospitals neonatal intensive care units (NICUs).

J Perinatol 2021 07 10;41(7):1745-1754. Epub 2021 Jun 10.

Department of Pediatrics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.

Objectives: To examine characteristics and outcomes of T18 and T13 infants receiving intensive surgical and medical treatment compared to those receiving non-intensive treatment in NICUs.

Study Design: Retrospective cohort of infants in the Children's Hospitals National Consortium (CHNC) from 2010 to 2016 categorized into three groups by treatment received: surgical, intensive medical, or non-intensive.

Results: Among 467 infants admitted, 62% received intensive medical treatment; 27% received surgical treatment. The most common surgery was a gastrostomy tube. Survival in infants who received surgeries was 51%; intensive medical treatment was 30%, and non-intensive treatment was 72%. Infants receiving surgeries spent more time in the NICU and were more likely to receive oxygen and feeding support at discharge.

Conclusions: Infants with T13 or T18 at CHNC NICUs represent a select group for whom parents may have desired more intensive treatment. Survival to NICU discharge was possible, and surviving infants had a longer hospital stay and needed more discharge supports.
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http://dx.doi.org/10.1038/s41372-021-01111-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191443PMC
July 2021

Commentary on a Neonate with Hypocalcemia and Cardiac Anomaly.

Authors:
Monica H Wojcik

Clin Chem 2021 06;67(6):827-828

Divisions of Newborn Medicine and Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1093/clinchem/hvab034DOI Listing
June 2021

Discordant results between conventional newborn screening and genomic sequencing in the BabySeq Project.

Genet Med 2021 07 26;23(7):1372-1375. Epub 2021 Mar 26.

Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.

Purpose: Newborn screening (NBS) is performed to identify neonates at risk for actionable, severe, early-onset disorders, many of which are genetic. The BabySeq Project randomized neonates to receive conventional NBS or NBS plus exome sequencing (ES) capable of detecting sequence variants that may also diagnose monogenic disease or indicate genetic disease risk. We therefore evaluated how ES and conventional NBS results differ in this population.

Methods: We compared results of NBS (including hearing screens) and ES for 159 infants in the BabySeq Project. Infants were considered "NBS positive" if any abnormal result was found indicating disease risk and "ES positive" if ES identified a monogenic disease risk or a genetic diagnosis.

Results: Most infants (132/159, 84%) were NBS and ES negative. Only one infant was positive for the same disorder by both modalities. Nine infants were NBS positive/ES negative, though seven of these were subsequently determined to be false positives. Fifteen infants were ES positive/NBS negative, all of which represented risk of genetic conditions that are not included in NBS programs. No genetic explanation was identified for eight infants referred on the hearing screen.

Conclusion: These differences highlight the complementarity of information that may be gleaned from NBS and ES in the newborn period.
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http://dx.doi.org/10.1038/s41436-021-01146-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263473PMC
July 2021

POLRMT mutations impair mitochondrial transcription causing neurological disease.

Nat Commun 2021 02 18;12(1):1135. Epub 2021 Feb 18.

Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.

While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism.
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http://dx.doi.org/10.1038/s41467-021-21279-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893070PMC
February 2021

Histone H3.3 beyond cancer: Germline mutations in cause a previously unidentified neurodegenerative disorder in 46 patients.

Sci Adv 2020 Dec 2;6(49). Epub 2020 Dec 2.

Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A () or with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
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http://dx.doi.org/10.1126/sciadv.abc9207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821880PMC
December 2020

Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects.

Am J Hum Genet 2020 12 23;107(6):1170-1177. Epub 2020 Nov 23.

Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address:

KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820620PMC
December 2020

Monogenic variants in dystonia: an exome-wide sequencing study.

Lancet Neurol 2020 11;19(11):908-918

Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Background: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.

Methods: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow.

Findings: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism.

Interpretation: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.

Funding: Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.
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http://dx.doi.org/10.1016/S1474-4422(20)30312-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246240PMC
November 2020

Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis.

Am J Med Genet A 2021 01 9;185(1):203-207. Epub 2020 Oct 9.

Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy-10 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in RTN4IP1, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo-reductase. Here we report novel compound heterozygous mutations in RTN4IP1 in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and choreoathetosis. Workup was notable for transiently elevated lactate and lactate-to-pyruvate ratio, brain magnetic resonance imaging with optic atrophy and T2 signal abnormalities, and a nondiagnostic initial genetic workup, including chromosomal microarray and mitochondrial panel testing. Exome sequencing identified a paternally inherited missense variant (c.263T>G, p.Val88Gly) predicted to be deleterious and a maternally inherited deletion encompassing RTN4IP1. To our knowledge, this is the first report of a non-single nucleotide pathogenic variant associated with OPA10. This case highlights the expanding phenotypic spectrum of OPA10, the association between "syndromic" cases and severe RTN4IP1 mutations, and the importance of nonbiased genetic testing, such as ES, to analyze multiple genes and variants types, in patients suspected of having genetic disease.
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http://dx.doi.org/10.1002/ajmg.a.61910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388561PMC
January 2021

The influence of social determinants of health on the genetic diagnostic odyssey: who remains undiagnosed, why, and to what effect?

Pediatr Res 2021 01 15;89(2):295-300. Epub 2020 Sep 15.

Division of Newborn Medicine, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA.

Although Mendelian genetic disorders are individually rare, they are collectively more common and contribute disproportionately to pediatric morbidity and mortality. Remarkable advances in the past decade have led to identification of the precise genetic variants responsible for many of these conditions. Confirming the molecular diagnosis through genetic testing allows for individualized treatment plans in addition to ending the diagnostic odyssey, which not only halts further unnecessary testing but may also result in immense psychological benefit, leading to improved quality of life. However, ensuring equitable application of these advances in genomic technology has been challenging. Though prior studies have revealed disparities in testing for genetic predisposition to cancer in adults, little is known about the prevalence and nature of disparities in diagnostic testing in the pediatric rare disease population. While it seems logical that those with impaired access to healthcare would be less likely to receive the genetic testing needed to end their odyssey, few studies have addressed this question directly and the potential impact on health outcomes. This review synthesizes the available evidence regarding disparities in pediatric genetic diagnosis, defining the need for further, prospective studies with the ultimate goal of delivering precision medicine to all who stand to benefit. IMPACT: Social determinants of health are known to contribute to inequality in outcomes, though the impact on pediatric rare disease patients is not fully understood. Diagnostic genetic testing is a powerful tool, though it may not be available to all in need. This article represents the first effort, to our knowledge, to evaluate the existing literature regarding disparities in genetic testing for pediatric rare disease diagnosis and identify gaps in care.
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http://dx.doi.org/10.1038/s41390-020-01151-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897209PMC
January 2021

Deciphering congenital anomalies for the next generation.

Cold Spring Harb Mol Case Stud 2020 10 7;6(5). Epub 2020 Oct 7.

Divisions of Newborn Medicine and Genetics and Genomics, Department of Pediatrics, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Congenital anomalies are common, with 2%-3% of infants estimated to have at least one major congenital malformation and countless others with minor malformations of lesser cosmetic or medical importance. As congenital malformations are major drivers of morbidity and mortality, representing the leading cause of infant mortality in the United States, there is substantial interest in understanding the underlying etiologies-particularly if modifiable causes may be identified or pre- or postnatal treatments can be offered. Recent research has begun to reveal the spectrum of monogenic disorders that commonly result in birth defects, and newer approaches have revealed non-Mendelian genetic contributions including gene-environment interactions. Our experience suggests that increased efforts to sequence and analyze cases of perinatal death, as well as continued global collaboration, will be essential in understanding the genomic landscape of structural anomalies.
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http://dx.doi.org/10.1101/mcs.a005504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552931PMC
October 2020

Genomic Insights into Stillbirth.

Authors:
Monica H Wojcik

N Engl J Med 2020 09 12;383(12):1182-1183. Epub 2020 Aug 12.

From the Divisions of Newborn Medicine and Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston.

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http://dx.doi.org/10.1056/NEJMe2016410DOI Listing
September 2020

Reconsidering Genetic Testing for Neonatal Polycystic Kidney Disease.

Kidney Int Rep 2020 Aug 23;5(8):1316-1319. Epub 2020 May 23.

Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1016/j.ekir.2020.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403496PMC
August 2020

Developmental Support for Infants With Genetic Disorders.

Pediatrics 2020 05;145(5)

Divisions of Newborn Medicine and.

As the technical ability for genetic diagnosis continues to improve, an increasing number of diagnoses are made in infancy or as early as the neonatal period. Many of these diagnoses are known to be associated with developmental delay and intellectual disability, features that would not be clinically detectable at the time of diagnosis. Others may be associated with cognitive impairment, but the incidence and severity are yet to be fully described. These neonates and infants with genetic diagnoses therefore represent an emerging group of patients who are at high risk for neurodevelopmental disabilities. Although there are well-established developmental supports for high-risk infants, particularly preterm infants, after discharge from the NICU, programs specifically for infants with genetic diagnoses are rare. And although previous research has demonstrated the positive effect of early developmental interventions on outcomes among preterm infants, the impact of such supports for infants with genetic disorders who may be born term, remains to be understood. We therefore review the literature regarding existing developmental assessment and intervention approaches for children with genetic disorders, evaluating these in the context of current developmental supports postdischarge for preterm infants. Further research into the role of developmental support programs for early assessment and intervention in high-risk neonates diagnosed with rare genetic disorders is needed.
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http://dx.doi.org/10.1542/peds.2019-0629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193975PMC
May 2020

Prenatal Diagnosis of a Ventral Abdominal Wall Defect.

Neoreviews 2020 04;21(4):e286-e292

Department of Radiology, Maternal Fetal Care Center, Boston Children's Hospital, Boston, MA.

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http://dx.doi.org/10.1542/neo.21-4-e286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402196PMC
April 2020

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content.

Hum Mol Genet 2020 06;29(9):1426-1439

Stem Cells and Metabolism Research Program, Research Programs Unit, University of Helsinki, 00290 Helsinki, Finland.

Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.
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http://dx.doi.org/10.1093/hmg/ddaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297229PMC
June 2020

Genetic diagnosis in the fetus.

J Perinatol 2020 07 24;40(7):997-1006. Epub 2020 Feb 24.

Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

Many genetic disorders are detectable in the prenatal period, and the capacity to identify them has increased remarkably as molecular genetic testing techniques continue to improve and become incorporated into clinical practice. The indications for prenatal genetic testing vary widely, including follow-up of an anomaly found by routine ultrasound or maternal aneuploidy screening, a family history of genetic disease, advanced maternal or paternal age, or evaluation of a low-risk pregnancy due to parental concern. The interpretation of genetic variants identified in the prenatal period poses unique challenges due to the lack of ability for deep phenotyping as well as the option to make critical decisions regarding pregnancy continuation and perinatal management. In this review, we address the various modalities currently available and commonly used for genetic testing, including preimplantation genetic testing of embryos, cell-free DNA testing, and diagnostic procedures such as chorionic villous sampling, amniocentesis, or percutaneous umbilical blood sampling, from which samples may be sent for a wide variety of genetic tests. We discuss the difference between these modalities for the genetic diagnosis of a fetus, their strengths and weaknesses, and strategies for their optimal use in order to direct perinatal care.
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http://dx.doi.org/10.1038/s41372-020-0627-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319864PMC
July 2020

Genome sequencing identifies a homozygous inversion disrupting QDPR as a cause for dihydropteridine reductase deficiency.

Mol Genet Genomic Med 2020 04 5;8(4):e1154. Epub 2020 Feb 5.

Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.

Background: Dihydropteridine reductase (DHPR) is one of the key enzymes for maintaining in the organism the supply of tetrahydrobiopterin (BH ), an essential cofactor for aromatic amino acid hydroxylases. Its dysfunction causes the condition of hyperphenylalaninemia together with the lack of neurotransmitters.

Methods: We report a patient with biochemically diagnosed DHPR deficiency, with extensive molecular investigations undertaken to detect variations in quinoid dihydropteridine reductase (QDPR) gene. Sanger sequencing of QDPR coding regions, exome sequencing, QDPR mRNA PCR, and karyotyping were followed by trio genome sequencing.

Results: Short-read genome sequencing revealed a homozygous 9-Mb inversion disrupting QDPR. Structural variant breakpoints in chromosome 4 were located to intron 2 of QDPR at Chr4(GRCh38):g.17505522 and in intron 8 of the ACOX3 gene, Chr4(GRCh38):g.8398067). Both nonrelated parents carried the variant in heterozygous state. The inversion was not present in gnomAD structural variant database.

Conclusion: Identification of the exact breakpoints now allows further straightforward molecular genetic testing of potential carriers of the inversion. This study extends the pathogenic variant spectrum of DHPR deficiency and highlights the role of structural variants in recessive metabolic disorders. To our knowledge, this is the first report on a large, canonical (rather than complex) homozygous pathogenic inversion detected by genome sequencing.
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http://dx.doi.org/10.1002/mgg3.1154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196484PMC
April 2020

Prospective, phenotype-driven selection of critically ill neonates for rapid exome sequencing is associated with high diagnostic yield.

Genet Med 2020 04 29;22(4):736-744. Epub 2019 Nov 29.

Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.

Purpose: To investigate the impact of rapid-turnaround exome sequencing in critically ill neonates using phenotype-based subject selection criteria.

Methods: Intensive care unit babies aged <6 months with hypotonia, seizures, a complex metabolic phenotype, and/or multiple congenital malformations were prospectively enrolled for rapid (<7 day) trio-based exome sequencing. Genomic variants relevant to the presenting phenotype were returned to the medical team.

Results: A genetic diagnosis was attained in 29 of 50 (58%) sequenced cases. Twenty-seven (54%) patients received a molecular diagnosis involving known disease genes; two additional cases (4%) were solved with pathogenic variants found in novel disease genes. In 24 of the solved cases, diagnosis had impact on patient management and/or family members. Management changes included shift to palliative care, medication changes, involvement of additional specialties, and the consideration of new experimental therapies.

Conclusion: Phenotype-based patient selection is effective at identifying critically ill neonates with a high likelihood of receiving a molecular diagnosis via rapid-turnaround exome sequencing, leading to faster and more accurate diagnoses, reducing unnecessary testing and procedures, and informing medical care.
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http://dx.doi.org/10.1038/s41436-019-0708-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127968PMC
April 2020

A missense mutation in the catalytic domain of O-GlcNAc transferase links perturbations in protein O-GlcNAcylation to X-linked intellectual disability.

FEBS Lett 2020 02 7;594(4):717-727. Epub 2019 Nov 7.

Division of Gene Regulation and Expression, School of Life Sciences, University of Dundee, UK.

X-linked intellectual disabilities (XLID) are common developmental disorders. The enzyme O-GlcNAc transferase encoded by OGT, a recently discovered XLID gene, attaches O-GlcNAc to nuclear and cytoplasmic proteins. As few missense mutations have been described, it is unclear what the aetiology of the patient phenotypes is. Here, we report the discovery of a missense mutation in the catalytic domain of OGT in an XLID patient. X-ray crystallography reveals that this variant leads to structural rearrangements in the catalytic domain. The mutation reduces in vitro OGT activity on substrate peptides/protein. Mouse embryonic stem cells carrying the mutation reveal reduced O-GlcNAcase (OGA) and global O-GlcNAc levels. These data suggest a direct link between changes in the O-GlcNAcome and intellectual disability observed in patients carrying OGT mutations.
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http://dx.doi.org/10.1002/1873-3468.13640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042088PMC
February 2020

Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging.

Am J Hum Genet 2019 09 22;105(3):493-508. Epub 2019 Aug 22.

Department of Psychiatry, University of Pretoria, Weskoppies Hospital, Pretoria, 0001 South Africa.

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731364PMC
September 2019

Infant mortality: the contribution of genetic disorders.

J Perinatol 2019 12 8;39(12):1611-1619. Epub 2019 Aug 8.

Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.

Objective: To determine the proportion of infant deaths occurring in the setting of a confirmed genetic disorder.

Study Design: A retrospective analysis of the electronic medical records of infants born from 1 January, 2011 to 1 June, 2017, who died prior to 1 year of age.

Results: Five hundred and seventy three deceased infants were identified. One hundred and seventeen were confirmed to have a molecular or cytogenetic diagnosis in a clinical diagnostic laboratory and an additional seven were diagnosed by research testing for a total of 124/573 (22%) diagnosed infants. A total of 67/124 (54%) had chromosomal disorders and 58/124 (47%) had single gene disorders (one infant had both). The proportion of diagnoses made by sequencing technologies, such as exome sequencing, increased over the years.

Conclusions: The prevalence of confirmed genetic disorders within our cohort of infant deaths is higher than that previously reported. Increased efforts are needed to further understand the mortality burden of genetic disorders in infancy.
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http://dx.doi.org/10.1038/s41372-019-0451-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879816PMC
December 2019

De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder.

Am J Hum Genet 2019 08 11;105(2):403-412. Epub 2019 Jul 11.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.
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http://dx.doi.org/10.1016/j.ajhg.2019.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698880PMC
August 2019

CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum.

Genet Med 2019 12 26;21(12):2723-2733. Epub 2019 Jun 26.

Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD).

Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function.

Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits.

Conclusion: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.
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http://dx.doi.org/10.1038/s41436-019-0585-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892744PMC
December 2019

Genome Sequencing Identifies the Pathogenic Variant Missed by Prior Testing in an Infant with Marfan Syndrome.

J Pediatr 2019 10 22;213:235-240. Epub 2019 Jun 22.

Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

We describe an infant with a phenotype typical of early onset Marfan syndrome whose genetic evaluation, including Sanger sequencing and deletion/duplication testing of FBN1 and exome sequencing, was negative. Ultimately, genome sequencing revealed a deletion missed on prior testing, demonstrating the unique utility of genome sequencing for molecular genetic diagnosis.
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http://dx.doi.org/10.1016/j.jpeds.2019.05.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765408PMC
October 2019

A retrospective analysis of the prevalence of imprinting disorders in Estonia from 1998 to 2016.

Eur J Hum Genet 2019 11 11;27(11):1649-1658. Epub 2019 Jun 11.

Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.

Imprinting disorders (ImpDis) represent a small group of rare congenital diseases primarily affecting growth, development, and the hormonal and metabolic systems. The aim of present study was to identify the prevalence of the ImpDis in Estonia, to describe trends in the live birth prevalence of these disorders between 1998 and 2016, and to compare the results with previously published data. We retrospectively reviewed the records of all Estonian patients since 1998 with both molecularly and clinically diagnosed ImpDis. A prospective study was also conducted, in which all patients with clinical suspicion for an ImpDis were molecularly analyzed. Eighty-seven individuals with ImpDis were identified. Twenty-seven (31%) of them had Prader-Willi syndrome (PWS), 15 (17%) had Angelman syndrome (AS), 15 (17%) had Silver-Russell syndrome (SRS), 12 (14%) had Beckwith-Wiedemann syndrome (BWS), 10 (11%) had pseudo- or pseudopseudohypoparathyroidism, four had central precocious puberty, two had Temple syndrome, one had transient neonatal diabetes mellitus, and one had myoclonus-dystonia syndrome. One third of SRS and BWS cases fulfilled the diagnostic criteria for these disorders, but tested negative for genetic abnormalities. Seventy-six individuals were alive as of January 1, 2018, indicating the total prevalence of ImpDis in Estonia is 5.8/100,000 (95% CI 4.6/100,000-7.2/100,000). The minimum live birth prevalence of all ImpDis in Estonia in 2004-2016 was 1/3,462, PWS 1/13,599, AS 1/27,198, BWS 1/21,154, SRS 1/15,866, and PHP/PPHP 1/27,198. Our results are only partially consistent with previously published data. The worldwide prevalence of SRS and GNAS-gene-related ImpDis is likely underestimated and may be at least three times higher than expected.
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http://dx.doi.org/10.1038/s41431-019-0446-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871525PMC
November 2019

Updating the neurodevelopmental profile of Alazami syndrome: Illustrating the role of developmental assessment in rare genetic disorders.

Am J Med Genet A 2019 08 10;179(8):1565-1569. Epub 2019 May 10.

Division of Developmental Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts.

Alazami syndrome, caused by biallelic pathogenic variants in LARP7, is a recently-described rare genetic disorder, with 17 patients currently reported in the literature. We present a case of a male infant referred for genetics evaluation at 5 months of age, found at 17 months of age to have Alazami syndrome. He was promptly referred for developmental evaluation, where he was found to be higher functioning than prior reports of individuals with this condition. This demonstrates the neurodevelopmental phenotypic variability seen in rare genetic disorders; it also demonstrates the important role of developmental programs to measure and track outcomes and provide support for infants with genetic disorders that put them at risk of developmental disabilities.
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http://dx.doi.org/10.1002/ajmg.a.61189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663627PMC
August 2019

PEHO syndrome caused by compound heterozygote variants in ZNHIT3 gene.

Eur J Med Genet 2020 Feb 29;63(2):103660. Epub 2019 Apr 29.

Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.

PEHO syndrome is characterized by Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy, which was first described in Finnish patients. A homozygous missense substitution p.Ser31Leu in ZNHIT3 was recently identified as the primary cause of PEHO syndrome in Finland. Variants in ZNHIT3 have not been identified in patients with PEHO or PEHO-like syndrome in other populations. It has therefore been suggested that PEHO syndrome caused by ZNHIT3 variants does not occur outside of the Finnish population. We describe the first patient outside Finland who carries compound heterozygous variants in ZNHIT3 gene causing PEHO syndrome. Trio genome sequencing was carried out and the identified variants were confirmed by Sanger sequencing. The patient filled all diagnostic clinical criteria of PEHO syndrome. We identified biallelic missense variants in ZNHIT3 gene: the c.92C > T p.(Ser31Leu) variant (NM_004773.3), which is described previously as causing PEHO syndrome and the second novel variant c.41G > T p.(Cys14Phe). There are only eight heterozygous carriers of c.41G > T variant in the gnomAD database and it is predicted damaging by multiple in silico algorithms. The ZNHIT3-associated PEHO syndrome exists outside of the Finnish population.
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http://dx.doi.org/10.1016/j.ejmg.2019.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819237PMC
February 2020
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