Publications by authors named "Beata A Nowakowska"

11 Publications

  • Page 1 of 1

Prenatal diagnosis of glutaric acidemia type 2 with the use of exome sequencing - an up-to-date review and new case report.

Ginekol Pol 2021 15;92(1):51-56. Epub 2021 Jan 15.

Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.

Introduction: Inborn errors of metabolism (IEM) also called metabolic diseases constitute a large and heterogenous group of disorders characterized by a failure of essential cellular functions. Antenatal manifestation of IEM is absent or nonspecific, which makes prenatal diagnosis challenging. Glutaric acidemia type 2 (GA2) is a rare metabolic disease clinically manifested in three different ways: neonatal-onset with congenital anomalies, neonatal-onset without congenital anomalies and late-onset. Neonatal forms are usually lethal. Congenital anomalies present on prenatal ultrasound as large, hyperechoic or cystic kidneys with reduced amniotic fluid volume.

Material And Methods: We present a systematic literature review describing prenatal diagnosis of GA2 and a new prenatal case.

Results: Ten prenatally diagnosed cases of GA2 have been published to date, mainly based on biochemical methods. New case of GA2 was diagnosed using exome sequencing method.

Discussion: All prenatal cases from literature review had positive history of GA2 running in the family. In our study trio exome sequencing was performed in case of fetal hyperechoic kidneys without a history of GA2. Consequently, we were able to identify two novel pathogenic variants of the ETFDH gene and to indicate their parental origin.

Summary: Exome sequencing approach used in case of fetal hyperechoic kidneys allows to identify pathogenic variants without earlier knowledge of the precise genetic background of the disease. Hyperechoic, enlarged kidneys could be one of the clinical features of metabolic diseases. After exclusion of chromosomal abnormalities, urinary tract obstruction and intrauterine infections, glutaric acidemia type 2 and number of monogenic disorders should be consider.
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http://dx.doi.org/10.5603/GP.a2020.0190DOI Listing
January 2021

Rubinstein-Taybi because of a novel EP300 mutation with novel clinical findings.

Clin Dysmorphol 2017 Jul;26(3):170-174

aDepartment of Pediatrics bJagiellonian University Medical College, Kraków cDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, Poland dJeroen KJ van Houdt, Center for Human Genetics, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1097/MCD.0000000000000164DOI Listing
July 2017

A catalog of hemizygous variation in 127 22q11 deletion patients.

Hum Genome Var 2016 14;3:15065. Epub 2016 Jan 14.

Department of Human Genetics, KU Leuven , Leuven, Belgium.

The 22q11.2 deletion syndrome is the most common microdeletion disorder, with wide phenotypic variability. To investigate variation within the non-deleted allele we performed targeted resequencing of the 22q11.2 region for 127 patients, identifying multiple deletion sizes, including two deletions with atypical breakpoints. We cataloged ~12,000 hemizygous variant positions, of which 84% were previously annotated. Within the coding regions 95 non-synonymous variants, three stop gains, and two frameshift insertions were identified, some of which we speculate could contribute to atypical phenotypes. We also catalog tolerability of 22q11 gene mutations based on related autosomal recessive disorders in man, embryonic lethality in mice, cross-species conservation and observations that some genes harbor more or less variants than expected. This extensive catalog of hemizygous variants will serve as a blueprint for future experiments to correlate 22q11DS variation with phenotype.
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http://dx.doi.org/10.1038/hgv.2015.65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892188PMC
June 2016

High-Resolution Array Comparative Genomic Hybridization Utility in Polish Newborns with Isolated Cleft Lip and Palate.

Neonatology 2015 21;107(3):173-8. Epub 2015 Jan 21.

Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.

Cleft lip with or without cleft palate is one of the most common birth defects of unknown etiology. A fraction of its genetic causes is attributable to copy number variations detected by array comparative genomic hybridization. The value of array comparative genomic hybridization screening as a first-tier test in the newborn population with multiple congenital anomalies has now been accepted. Due to unspecific clinical picture at this age, it can also be applied to neonates with isolated anomalies. Our purpose was to assess utility of array comparative genomic hybridization in the population of newborns with isolated cleft lip and palate. We conducted the study in a group of 52 Polish newborns with apparently isolated cleft lip and palate. In the study group, we found 8 rearrangements. Of these, 2 de novo events have been noted that potentially explain the phenotype. In addition, 2 novel candidate genes for cleft lip and palate, CHN2 and CDH19, are suggested. Given the high number of inherited potentially benign changes, we question the clinical utility of array comparative genomic hybridization in the newborn population with isolated cleft lip and palate, at the same time pointing to the need of skilled professional's clinical assessment at a later age. However, the value of this technology in searching for the cause of isolated anomalies cannot be underestimated.
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http://dx.doi.org/10.1159/000368878DOI Listing
January 2016

The analysis of genetic aberrations in children with inherited neurometabolic and neurodevelopmental disorders.

Biomed Res Int 2014 13;2014:424796. Epub 2014 May 13.

Clinic of Child and Adolescent Neurology, Institute of Mother and Child, 01-211 Warsaw, Poland.

Inherited encephalopathies include a broad spectrum of heterogeneous disorders. To provide a correct diagnosis, an integrated approach including genetic testing is warranted. We report seven patients with difficult to diagnose inborn paediatric encephalopathies. The diagnosis could not be attained only by means of clinical and laboratory investigations and MRI. Additional genetic testing was required. Cytogenetics, PCR based tests, and array-based comparative genome hybridization were performed. In 4 patients with impaired language abilities we found the presence of microduplication in the region 16q23.1 affecting two dose-sensitive genes: WWOX (OMIM 605131) and MAF (OMIM 177075) (1 case), an interstitial deletion of the 17p11.2 region (2 patients further diagnosed as Smith-Magenis syndrome), and deletion encompassing first three exons of Myocyte Enhancer Factor gene 2MEF2C (1 case). The two other cases represented progressing dystonia. Characteristic GAG deletion in DYT1 consistently with the diagnosis of torsion dystonia was confirmed in 1 case. Last enrolled patient presented with clinical picture consistent with Krabbe disease confirmed by finding of two pathogenic variants of GALC gene and the absence of mutations in PSAP. The integrated diagnostic approach including genetic testing in selected examples of complicated hereditary diseases of the brain is largely discussed in this paper.
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http://dx.doi.org/10.1155/2014/424796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052700PMC
February 2015

Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS.

J Med Genet 2013 Feb 11;50(2):80-90. Epub 2012 Dec 11.

Division of Human Genetics, The Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Background: 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder, affecting an estimated 1 : 2000-4000 live births. Patients with 22q11.2DS have a broad spectrum of phenotypic abnormalities which generally includes congenital cardiac abnormalities, palatal anomalies, and immunodeficiency. Additional findings, such as skeletal anomalies and autoimmune disorders, can confer significant morbidity in a subset of patients. 22q11.2DS is a contiguous gene DS and over 40 genes are deleted in patients; thus deletion of several genes within this region contributes to the clinical features. Mutations outside or on the remaining 22q11.2 allele are also known to modify the phenotype.

Methods: We utilised whole exome, targeted exome and/or Sanger sequencing to examine the genome of 17 patients with 22q11.2 deletions and phenotypic features found in <10% of affected individuals.

Results And Conclusions: In four unrelated patients, we identified three novel mutations in SNAP29, the gene implicated in the autosomal recessive condition cerebral dysgenesis, neuropathy, ichthyosis and keratoderma (CEDNIK). SNAP29 maps to 22q11.2 and encodes a soluble SNARE protein that is predicted to mediate vesicle fusion at the endoplasmic reticulum or Golgi membranes. This work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to mutations on the non-deleted chromosome, which leads to unmasking of autosomal recessive conditions such as CEDNIK, Kousseff, and a potentially autosomal recessive form of Opitz G/BBB syndrome. Furthermore, our work implicates SNAP29 as a major modifier of variable expressivity in 22q11.2 DS patients.
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http://dx.doi.org/10.1136/jmedgenet-2012-101320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585484PMC
February 2013

Nonallelic homologous recombination between retrotransposable elements is a driver of de novo unbalanced translocations.

Genome Res 2013 Mar 3;23(3):411-8. Epub 2012 Dec 3.

Laboratory for Molecular Cytogenetics and Genome Research, Department of Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.

Large-scale analysis of balanced chromosomal translocation breakpoints has shown nonhomologous end joining and microhomology-mediated repair to be the main drivers of interchromosomal structural aberrations. Breakpoint sequences of de novo unbalanced translocations have not yet been investigated systematically. We analyzed 12 de novo unbalanced translocations and mapped the breakpoints in nine. Surprisingly, in contrast to balanced translocations, we identify nonallelic homologous recombination (NAHR) between (retro)transposable elements and especially long interspersed elements (LINEs) as the main mutational mechanism. This finding shows yet another involvement of (retro)transposons in genomic rearrangements and exposes a profoundly different mutational mechanism compared with balanced chromosomal translocations. Furthermore, we show the existence of compound maternal/paternal derivative chromosomes, reinforcing the hypothesis that human cleavage stage embryogenesis is a cradle of chromosomal rearrangements.
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http://dx.doi.org/10.1101/gr.145631.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589530PMC
March 2013

Parental insertional balanced translocations are an important cause of apparently de novo CNVs in patients with developmental anomalies.

Eur J Hum Genet 2012 Feb 14;20(2):166-70. Epub 2011 Sep 14.

Department of Human Genetics, KU Leuven, Leuven, Belgium.

In several laboratories, genome-wide array analysis has been implemented as the first tier diagnostic test for the identification of copy number changes in patients with mental retardation and/or congenital anomalies. The identification of a pathogenic copy number variant (CNV) is not only important to make a proper diagnosis but also to enable the accurate estimation of the recurrence risk to family members. Upon the identification of a de novo interstitial loss or gain, the risk recurrence is considered very low. However, this risk is 50% if one of the parents is carrier of a balanced insertional translocation (IT). The apparently de novo imbalance in a patient is then the consequence of the unbalanced transmission of a derivative chromosome involved in an IT. To determine the frequency with which insertional balanced translocations would be the origin of submicroscopic imbalances, we investigated the potential presence of an IT in a consecutive series of 477 interstitial CNVs, in which the parental origin has been tested by FISH, among 14,293 patients with developmental abnormalities referred for array. We demonstrate that ITs underlie ~2.1% of the apparently de novo, interstitial CNVs, indicating that submicroscopic ITs are at least sixfold more frequent than cytogenetically visible ITs. This risk estimate should be taken into account during counseling, and warrant parental and proband FISH testing wherever possible in patients with an apparently de novo, interstitial aberration.
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http://dx.doi.org/10.1038/ejhg.2011.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260932PMC
February 2012

Detection of clinically relevant exonic copy-number changes by array CGH.

Hum Mutat 2010 Dec 2;31(12):1326-42. Epub 2010 Nov 2.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.

Array comparative genomic hybridization (aCGH) is a powerful tool for the molecular elucidation and diagnosis of disorders resulting from genomic copy-number variation (CNV). However, intragenic deletions or duplications--those including genomic intervals of a size smaller than a gene--have remained beyond the detection limit of most clinical aCGH analyses. Increasing array probe number improves genomic resolution, although higher cost may limit implementation, and enhanced detection of benign CNV can confound clinical interpretation. We designed an array with exonic coverage of selected disease and candidate genes and used it clinically to identify losses or gains throughout the genome involving at least one exon and as small as several hundred base pairs in size. In some patients, the detected copy-number change occurs within a gene known to be causative of the observed clinical phenotype, demonstrating the ability of this array to detect clinically relevant CNVs with subkilobase resolution. In summary, we demonstrate the utility of a custom-designed, exon-targeted oligonucleotide array to detect intragenic copy-number changes in patients with various clinical phenotypes.
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http://dx.doi.org/10.1002/humu.21360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158569PMC
December 2010

Exon deletions of the EP300 and CREBBP genes in two children with Rubinstein-Taybi syndrome detected by aCGH.

Eur J Hum Genet 2011 Jan 18;19(1):43-9. Epub 2010 Aug 18.

The Children's Hospital, Section of Clinical Genetics and Metabolism, Denver, UC Denver, Aurora, CO, USA.

We demonstrate the utility of an exon coverage microarray platform in detecting intragenic deletions: one in exons 24-27 of the EP300 gene and another in exons 27 and 28 of the CREBBP gene in two patients with Rubinstein-Taybi syndrome (RSTS). RSTS is a heterogeneous disorder in which approximately 45-55% of cases result from deletion or mutations in the CREBBP gene and an unknown portion of cases result from gene changes in EP300. The first case is a 3-year-old female with an exonic deletion of the EP300 gene who has classic facial features of RSTS without the thumb and great toe anomalies, consistent with the milder skeletal phenotype that has been described in other RSTS cases with EP300 mutations. In addition, the mother of this patient also had preeclampsia during pregnancy, which has been infrequently reported. The second case is a newborn male who has the classical features of RSTS. Our results illustrate that exon-targeted array comparative genomic hybridization (aCGH) is a powerful tool for detecting clinically significant intragenic rearrangements that would be otherwise missed by aCGH platforms lacking sufficient exonic coverage or sequencing of the gene of interest.
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http://dx.doi.org/10.1038/ejhg.2010.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039495PMC
January 2011

Severe mental retardation, seizures, and hypotonia due to deletions of MEF2C.

Am J Med Genet B Neuropsychiatr Genet 2010 Jul;153B(5):1042-51

Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.

We present four patients, in whom we identified overlapping deletions in 5q14.3 involving MEF2C using a clinical oligonucleotide array comparative genomic hybridization (CGH) chromosomal microarray analysis (CMA). In case 1, CMA revealed an approximately 140 kb deletion encompassing the first three exons of MEF2C in a 3-year-old patient with severe psychomotor retardation, periodic tremor, and an abnormal motor pattern with mirror movement of the upper limbs observed during infancy, hypotonia, abnormal EEG, epilepsy, absence of speech, autistic behavior, bruxism, and mild dysmorphic features. MRI of the brain showed mild thinning of the corpus callosum and delay of white matter myelination in the occipital lobes. In case 2, an approximately 1.8 Mb deletion of TMEM161B and MEF2C was found in a child with severe developmental delay, hypotonia, and seizures. Patient 3 had epilepsy, hypotonia, thinning of the corpus callosum, and developmental delay associated with a de novo approximately 2.4 Mb deletion in 5q14.3 including MEF2C and five other genes. In case 4, a de novo approximately 5.7 Mb deletion of MEF2C and five other genes was found in a child with truncal hypotonia, intractable seizures, profound developmental delay, and shortening of the corpus callosum on brain MRI. These deletions further support that haploinsufficiency of MEF2C is responsible for severe mental retardation, seizures, and hypotonia. Our results, in combination with previous reports, imply that exon-targeted oligo array CGH, which is more efficient in identifying exonic copy number variants, should improve the detection of clinically significant deletions and duplications over arrays with probes spaced evenly throughout the genome.
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http://dx.doi.org/10.1002/ajmg.b.31071DOI Listing
July 2010