Publications by authors named "Alida C Knegt"

21 Publications

  • Page 1 of 1

The prevalence of genetic diagnoses in fetuses with severe congenital heart defects.

Genet Med 2020 Jul 28;22(7):1206-1214. Epub 2020 Apr 28.

Department of Obstetrics and Fetal Medicine, Leiden University Medical Center, Leiden, Netherlands.

Purpose: Congenital heart defects (CHD) are associated with genetic syndromes. Rapid aneuploidy testing and chromosome microarray analysis (CMA) are standard care in fetal CHD. Many genetic syndromes remain undetected with these tests. This cohort study aims to estimate the frequency of causal genetic variants, in particular structural chromosome abnormalities and sequence variants, in fetuses with severe CHD at mid-gestation, to aid prenatal counselling.

Methods: Fetuses with severe CHD were extracted from the PRECOR registry (2012-2016). We evaluated pre- and postnatal genetic testing results retrospectively to estimate the frequency of genetic diagnoses in general, as well as for specific CHDs.

Results: 919 fetuses with severe CHD were identified. After exclusion of 211 cases with aneuploidy, a genetic diagnosis was found in 15.7% (111/708). These comprised copy number variants in 9.9% (70/708). In 4.5% (41/708) sequence variants were found that would have remained undetected with CMA. Interrupted aortic arch, pulmonary atresia with ventricular septal defect and atrioventricular septal defect were most commonly associated with a genetic diagnosis.

Conclusion: In case of normal CMA results, parents should be offered exome sequencing sequentially, if time allows for it, especially if the CHD is accompanied by other structural malformations due to the large variety in genetic syndromes.
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http://dx.doi.org/10.1038/s41436-020-0791-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332415PMC
July 2020

Prenatal sonographic features can accurately determine parental origin in triploid pregnancies.

Prenat Diagn 2020 05 3;40(6):705-714. Epub 2020 Mar 3.

Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Objective: To describe the prenatal sonographic features and maternal biochemical markers in triploid pregnancies and to assess whether prenatal phenotype can determine genetic origin.

Methods: We performed a retrospective multicenter cohort study that included all triploid pregnancies diagnosed between 2000 and 2018 in two Fetal Medicine Units in Amsterdam. Fetal growth, presence of structural anomalies, extra-fetal anomalies, and maternal biochemical markers were retrieved. Asymmetrical intrauterine growth restriction was diagnosed when the head-to-abdominal circumference (HC/AC) ratio was >95th centile. Parental origin was analyzed via molecular genotyping in 46 cases (38.3%).

Results: One hundred and twenty triploid pregnancies were identified, of which 86 cases (71.6%) were detected before 18 weeks of gestation. Triploidy of maternal origin was found in 32 cases (69.6%) and was associated with asymmetrical growth restriction, a thin placenta, and low pregnancy-associated plasma protein A and free beta-human chorionic gonadotrophin (β-hCG) levels. Triploidy of paternal origin was found in 14 cases (30.4%) and was associated with an increased nuchal translucency, placental molar changes, and a high free β-hCG. Prospective prediction of the parental origin of the triploidy was made in 30 of the 46 cases based on phenotypical ultrasound presentation, and it was correct in all cases.

Conclusion: Asymmetrical growth restriction with severe HC/AC discrepancy is pathognomonic of maternal triploidy. Placental molar changes indicate a paternal triploidy. Moreover, triploidy can present with an abnormal first trimester combined test, with serum levels on the extreme end. When available results of maternal serum markers can support the diagnosis of parental origin of the triploidy, an accurate assessment of the parental origin based on prenatal sonographic features is possible, making DNA analysis redundant.
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http://dx.doi.org/10.1002/pd.5666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317806PMC
May 2020

Mosaic maternal 10qter deletions are associated with FRA10B expansions and may cause false-positive noninvasive prenatal screening results.

Genet Med 2018 11 1;20(11):1472-1476. Epub 2018 Mar 1.

Department of Clinical Genetics, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.

Purpose: Using genome-wide noninvasive prenatal screening (NIPS), we detected a 20-megabase specific deletion starting at 10q25 in eight pregnancies. The deletion could not be confirmed by invasive testing. Since all 10(q25→qter) deletions started close to the FRA10B fragile site in 10q25, we investigated whether the pregnant women were indeed carriers of FRA10B.

Methods: We performed NIPS analysis for all autosomes using single-read sequencing. Analysis was done with the WISECONDOR algorithm. Culture of blood lymphocytes with bromodeoxyuridine was used to detect FRA10B expansions. Fluorescence in situ hybridization and array analysis were used to find maternal and/or fetal deletions.

Results: We confirmed the presence of a FRA10B expansion in all four tested mothers. Fluorescence in situ hybridization and array analysis confirmed the presence of a maternal mosaic deletion of 10(q25→qter).

Conclusion: The recurring 10(q25→qter) deletion detected with NIPS is a false-positive result caused by a maternal low-level mosaic deletion associated with FRA10B expansions. This has important consequences for clinical follow-up, as invasive procedures are unnecessary. Expanded maternal FRA10B repeats should be added to the growing group of variants in the maternal genome that may cause false-positive NIPS results.
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http://dx.doi.org/10.1038/gim.2018.32DOI Listing
November 2018

Absence epilepsy and the CHD2 gene: an adolescent male with moderate intellectual disability, short-lasting psychoses, and an interstitial deletion in 15q26.1-q26.2.

Neuropsychiatr Dis Treat 2016 10;12:1135-9. Epub 2016 May 10.

Department of Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.

Deletions of the 15q26 region encompassing the chromodomain helicase DNA binding domain 2 (CHD2) gene have been associated with intellectual disability, behavioral problems, and several types of epilepsy. Including the cases mentioned in ECARUCA (European cytogeneticists association register of unbalanced chromosome aberrations) and DECIPHER (database of genomic variation and phenotype in humans using ensembl resources), so far, a total of 13 intellectually disabled patients with a genetically proven deletion of the CHD2 gene are described, of whom eleven had a history of severe forms of epilepsy starting from a young age. In this article, a moderately intellectually disabled 15-year-old male with a 15q26.1-q26.2 interstitial deletion is reported, who was referred for analysis of two recent short-lasting psychotic episodes that were nonresponsive to antipsychotic treatment and recurrent disinhibited behaviors since early infancy. Careful interdisciplinary assessment revealed that the psychotic phenomena originated from a previously unrecognized absence epilepsy. Treatment with valproic acid was started which resulted in full remission of psychotic symptoms, and consequently, substantial improvement of behavior. It was concluded that in case of (rare) developmental disorders with genetically proven etiology, a detailed inventory of anamnestic data and description of symptomatology over time may elucidate epilepsy-related psychopathology for which a specific treatment regimen is needed.
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http://dx.doi.org/10.2147/NDT.S102272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869798PMC
June 2016

Chromosomal abnormalities and copy number variations in fetal left-sided congenital heart defects.

Prenat Diagn 2016 Feb 3;36(2):177-85. Epub 2016 Feb 3.

Department of Obstetrics and Fetal Medicine, Leiden University Medical Center, Leiden, the Netherlands.

Objectives: To demonstrate the spectrum of copy number variants (CNVs) in fetuses with isolated left-sided congenital heart defects (CHDs), and analyse genetic content.

Methods: Between 2003 and 2012, 200 fetuses were identified with left-sided CHD. Exclusion criteria were chromosomal rearrangements, 22q11.2 microdeletion and/or extra-cardiac malformations (n = 64). We included cases with additional minor anomalies (n = 39), such as single umbilical artery. In 54 of 136 eligible cases, stored material was available for array analysis. CNVs were categorized as either (likely) benign, (likely) pathogenic or of unknown significance.

Results: In 18 of the 54 isolated left-sided CHDs we found 28 rare CNVs (prevalence 33%, average 1.6 CNV per person, size 10.6 kb-2.2 Mb). Our interpretation yielded clinically significant CNVs in two of 54 cases (4%) and variants of unknown significance in three other cases (6%).

Conclusions: In left-sided CHDs that appear isolated, with normal chromosome analysis and 22q11.2 FISH analysis, array analysis detects clinically significant CNVs. When counselling parents of a fetus with a left-sided CHD it must be taken into consideration that aside from the cardiac characteristics, the presence of extra-cardiac malformations and chromosomal abnormalities influence the treatment plan and prognosis.
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http://dx.doi.org/10.1002/pd.4767DOI Listing
February 2016

Genetic basis of alpha-aminoadipic and alpha-ketoadipic aciduria.

J Inherit Metab Dis 2015 Sep 10;38(5):873-9. Epub 2015 Apr 10.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Box 1498, New York, NY, 10029, USA.

Alpha-aminoadipic and alpha-ketoadipic aciduria is an autosomal recessive inborn error of lysine, hydroxylysine, and tryptophan degradation. To date, DHTKD1 mutations have been reported in two alpha-aminoadipic and alpha-ketoadipic aciduria patients. We have now sequenced DHTKD1 in nine patients diagnosed with alpha-aminoadipic and alpha-ketoadipic aciduria as well as one patient with isolated alpha-aminoadipic aciduria, and identified causal mutations in eight. We report nine novel mutations, including three missense mutations, two nonsense mutations, two splice donor mutations, one duplication, and one deletion and insertion. Two missense mutations, one of which was reported before, were observed in the majority of cases. The clinical presentation of this group of patients was inhomogeneous. Our results confirm that alpha-aminoadipic and alpha-ketoadipic aciduria is caused by mutations in DHTKD1, and further establish that DHTKD1 encodes the E1 subunit of the alpha-ketoadipic acid dehydrogenase complex.
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http://dx.doi.org/10.1007/s10545-015-9841-9DOI Listing
September 2015

Genomic and functional overlap between somatic and germline chromosomal rearrangements.

Cell Rep 2014 Dec 11;9(6):2001-10. Epub 2014 Dec 11.

Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands. Electronic address:

Genomic rearrangements are a common cause of human congenital abnormalities. However, their origin and consequences are poorly understood. We performed molecular analysis of two patients with congenital disease who carried de novo genomic rearrangements. We found that the rearrangements in both patients hit genes that are recurrently rearranged in cancer (ETV1, FOXP1, and microRNA cluster C19MC) and drive formation of fusion genes similar to those described in cancer. Subsequent analysis of a large set of 552 de novo germline genomic rearrangements underlying congenital disorders revealed enrichment for genes rearranged in cancer and overlap with somatic cancer breakpoints. Breakpoints of common (inherited) germline structural variations also overlap with cancer breakpoints but are depleted for cancer genes. We propose that the same genomic positions are prone to genomic rearrangements in germline and soma but that timing and context of breakage determines whether developmental defects or cancer are promoted.
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http://dx.doi.org/10.1016/j.celrep.2014.11.022DOI Listing
December 2014

[Deletion 15q26 syndrome].

Orv Hetil 2014 Mar;155(9):362-4

University of Amsterdam Academisch Medisch Centrum Amsterdam Hollandia.

The association of short stature, microcephaly, congenital cardiac anomaly and intellectual deficit should always raise the suspicion of chromosomal etiology. If G-banded karyotyping fails to detect large chromosomal aberrations, array comparative genomic hybridization (array CGH) should be performed to screen for submicroscopic pathological copy number changes. The authors present a six-year-old girl whose symptoms arose from a 4.1 Mb loss in the 15q26.2-26.3 telomeric region. The syndrome is characterized by a resistance to the insulin-like growth factor 1 - in our case the increased level of the insulin-like growth factor 1 together with the persistent longitudinal growth failure was an important finding and differential diagnostic feature. A brief overview of the literature is provided.
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http://dx.doi.org/10.1556/OH.2014.29826DOI Listing
March 2014

Positive predictive values for detection of trisomies 21, 18 and 13 and termination of pregnancy rates after referral for advanced maternal age, first trimester combined test or ultrasound abnormalities in a national screening programme (2007-2009).

Prenat Diagn 2014 Mar 23;34(3):259-64. Epub 2014 Jan 23.

Reference Laboratory for Pre- and Neonatal Screening/Laboratory for Infectious Diseases and Screening, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

Objective: The objective of this article is to analyse the positive predictive value (PPV) of trisomies 21, 18 and 13 after referral for advanced maternal age (AMA), first trimester combined test or ultrasound findings to suggest improvements for clinical practice.

Methods: Data (48 457 combined tests, 134 000 fetal anomaly scans and 24 379 invasive prenatal tests) were combined to calculate PPV and termination of pregnancy rates.

Results: For referral for AMA, the PPV for T21 was 1.0% and 1.8% for amniocentesis and chorionic villus biopsy, respectively; for the combined test at a maternal age ≥36 years, these percentages were 4.9% and 12.5%, respectively and for maternal age <36 years, 4.4% and 8.1%, respectively. For ultrasound findings, the PPV was 5.3% and 14.8%, respectively. Termination of pregnancy rate upon trisomy 21 diagnosis was >90% unless detected after referral for ultrasound findings (71.5-85.9%). About 50% of pregnant women with a high combined test risk chose not to have invasive testing.

Conclusions: Advanced MA is still a large contributor to invasive testing but should be abandoned (low PPV, high fetal loss rate) and be replaced by reimbursable combined test screening for all women. Patient information on second trimester ultrasound screening should indicate that abnormal ultrasound findings are associated with high trisomy rate.
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http://dx.doi.org/10.1002/pd.4302DOI Listing
March 2014

Achondroplasia with multiple-suture craniosynostosis: a report of a new case of this rare association.

Am J Med Genet A 2013 Oct 15;161A(10):2641-4. Epub 2013 Aug 15.

Clinical Genetic Center, Department of Pediatrics, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.

We report on a female patient with an exceedingly rare combination of achondroplasia and multiple-suture craniosynostosis. Besides the specific features of achondroplasia, synostosis of the metopic, coronal, lambdoid, and squamosal sutures was found. Series of neurosurgical interventions were carried out, principally for acrocephaly and posterior plagiocephaly. The most common achondroplasia mutation, a p.Gly380Arg in the fibroblast growth factor receptor 3 (FGFR3) gene, was detected. Cytogenetic and array CGH analyses, as well as molecular genetic testing of FGFR1, 2, 3 and TWIST1 genes failed to identify any additional genetic alteration. It is suggested that this unusual phenotype is a result of variable expressivity of the common achondroplasia mutation.
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http://dx.doi.org/10.1002/ajmg.a.36130DOI Listing
October 2013

6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment.

Am J Med Genet A 2013 Jul 17;161A(7):1682-5. Epub 2013 May 17.

Institute of Medical Genetics, UMC, Ljubljana, Slovenia.

The chromosome 6p21.3 microdeletion phenotype was recently identified through array comparative genomic hybridization. The main features are developmental delay with severe speech impairment, seizures, and behavioral abnormalities. Three patients have been reported with deletion sizes ranging from 100 to 800 kb. We report on a 9-year-old boy with an apparently de novo, 50 kb deletion, and global developmental delay, severe speech impairment, and generalized epilepsy well-controlled by medication. There were four genes identified in this deletion, of which SYNGAP1 is considered to be responsible for speech impairment and epilepsy. We compared the clinical features of this patient with previously reported patients with 6p21.3 and patients with SYNGAP1 mutations. © 2013 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.35930DOI Listing
July 2013

Genetic basis of hyperlysinemia.

Orphanet J Rare Dis 2013 Apr 9;8:57. Epub 2013 Apr 9.

Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, AZ 1105, The Netherlands.

Background: Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of hyperlysinemia.

Methods: We collected the clinical, biochemical and molecular data in a cohort of 8 hyperlysinemia patients with distinct neurological features.

Results: We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1.

Conclusions: Hyperlysinemia is caused by mutations in AASS. As hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1. Our findings illustrate the importance of detailed biochemical and genetic studies in any hyperlysinemia patient.
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http://dx.doi.org/10.1186/1750-1172-8-57DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3626681PMC
April 2013

Intellectual disability and hemizygous GPD2 mutation.

Am J Med Genet A 2013 May 29;161A(5):1044-50. Epub 2013 Mar 29.

Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

We report on a 25-year-old female with intellectual disability, mildly unusual face, and a pervasive developmental disorder, in whom routine aCGH showed a 298 kb de novo deletion at chromosome 2q24.1(156869529-157167986 × 1). The region contained two genes (NR4A2; GPD2). Molecular studies in the proposita showed an additional variant in GPD2 (c.614C > T, p.Pro205Leu), which was predicted to be pathogenic. The variant was also present in the healthy mother and sister. Functional analysis showed absent GPD2 activity in the proposita and 50% activity in mother and sister. We conclude that we have been able to find circumstantial evidence for the causative effect of the hemizygous GPD2 mutation but full proof remained lacking. Total costs for the work-up in these patients were high (€21,975 [$27,029]). Similar results will increasingly be found when Next Generation Techniques will be applied widely in patients with intellectual disability, and proving pathogenicity by functional studies or in animal models will be expensive. We advocate the use of freely accessible international databases combining phenotype and genotype data using standard nomenclatures to facilitate proving pathogenicity of research data and to decrease costs of health care.
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http://dx.doi.org/10.1002/ajmg.a.35873DOI Listing
May 2013

De novo mutations of the gene encoding the histone acetyltransferase KAT6B in two patients with Say-Barber/Biesecker/Young-Simpson syndrome.

Am J Med Genet A 2013 Apr 22;161A(4):884-8. Epub 2013 Feb 22.

Institute of Pediatrics, Clinical Genetics Center, University of Debrecen, Medical & Health Science Center, Debrecen, Hungary.

The Say-Barber/Biesecker/Young-Simpson (SBBYS) type of the blepharophimosis-mental retardation syndrome group (Ohdo-like syndromes) is a multiple congenital malformation syndrome characterized by vertical narrowing and shortening of the palpebral fissures, ptosis, intellectual disability, hypothyroidism, hearing impairment, and dental anomalies. Mutations of the gene encoding the histone-acetyltransferase KAT6B have been recently identified in individuals affected by SBBYS syndrome. SBBYS syndrome-causing KAT6B mutations cluster in a ~1,700 basepair region in the 3' part of the large exon 18, while mutations located in the 5' region of the same exon have recently been identified to cause the genitopatellar syndrome (GPS), a clinically distinct although partially overlapping malformation-intellectual disability syndrome. Here, we present two children with clinical features of SBBYS syndrome and de novo truncating KAT6B mutations, including a boy who was diagnosed at the age of 4 months. Our results confirm the implication of KAT6B mutations in typical SBBYS syndrome and emphasize the importance of genotype-phenotype correlations at the KAT6B locus where mutations truncating the KAT6B protein at the amino-acid positions ~1,350-1,920 cause SBBYS syndrome.
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http://dx.doi.org/10.1002/ajmg.a.35848DOI Listing
April 2013

Subtelomeric 6.7 Mb trisomy 10p and 5.6 Mb monosomy 21q detected by FISH and array-CGH in three related patients.

Am J Med Genet A 2012 Apr 9;158A(4):869-76. Epub 2012 Mar 9.

Pediatrics Institute, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary.

Cryptic subtelomeric chromosomal aberrations are responsible for 5-10% of moderate/severe and 1% of mild intellectual disability. Unbalanced subtelomeric chromosomal rearrangements result in variable phenotypes which seem to be highly influenced by both the size of the duplication/deletion and the chromosomes involved in the translocation. We report on three related patients with moderate intellectual disability, language delay, hypotonia, facial dysmorphism, cardiac anomalies, scoliosis, and kyphosis in whom a familial (maternal) unbalanced submicroscopic translocation was found by subtelomeric fluorescence in situ hybridization (FISH). This rearrangement resulted in a partial trisomy 10pter and partial monosomy 21qter. The karyotype was 46,XY.ish der(21)t(10;21)(p14;q22.2). Confirmation of a 6.7 Mb size distal duplication of the p15.3-14 region of chromosome 10 and a 5.6 Mb distal deletion of the q22.2-22.3 region of chromosome 21 was obtained by array-CGH. To our best knowledge, such a composition of subtelomeric unbalanced translocations has not yet been published. Detection of this aberration in successive pregnancies of carrier members of the family by prenatal FISH could prevent the recurrence of the disease. Furthermore, detection of the rearrangements and identification of genes located in the chromosomal regions involved might be of interest.
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http://dx.doi.org/10.1002/ajmg.a.35236DOI Listing
April 2012

Prenatal diagnosis of a trisomy 7/trisomy 13 mosaicism.

Mol Cytogenet 2012 Jan 27;5(1). Epub 2012 Jan 27.

Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

Double aneuploidy mosaicism of two different aneuploidy cell lines is rare. We describe for the first time a double trisomy mosaicism, involving chromosomes 7 and 13 in a fetus presenting with multiple congenital anomalies. No evidence for chimerism was found by DNA genotyping. The origin of both trisomies are consistent with isodisomy of maternal origin. Therefore, it is most likely that the double trisomy mosaicism arose from two independent events very early in embryonic development. The trisomy 7 and 13 cells were shown to be of maternal origin.
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http://dx.doi.org/10.1186/1755-8166-5-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293093PMC
January 2012

Endocrine and anatomical findings in a case of Solitary Median Maxillary Central Incisor Syndrome.

Eur J Med Genet 2012 Feb 17;55(2):109-11. Epub 2011 Nov 17.

Inst. of Pediatrics, Clinical Genetics Center, University of Debrecen, Medical & Health Science Center, 4012 Debrecen, Nagyerdei krt. 98., Hungary.

Solitary Median Maxillary Central Incisor Syndrome (SMMCI) is a rare malformation syndrome consisting of multiple, mainly midline defects. Some authors suggest that it is a mild manifestation of the wide spectrum of holoprosencephaly, others classify it rather as a distinct entity. Authors report a case of SMMCI presenting with growth retardation, mild intellectual disability and absence of puberty. Cytogenetic and molecular cytogenetic investigations could identify no abnormalities. The presence of a single maxillary incisor called for further investigations to clarify hidden anomalies, these were empty sella, panhypopituitarism, hypothyroidism, and hypoplasia of the inner genitals. Based on the above findings, growth hormone, estrogen, and L-thyroxine substitution was introduced, which resulted in satisfactory longitudinal growth and onset of sexual maturation. We suggest genetic counselling and if needed, invasive investigations in female patients with short stature and absent/delayed puberty, with or without sex chromosomal anomalies, as the adequate therapy and even the quality of life of patient depends largely on the knowledge of their anatomical and endocrine status.
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http://dx.doi.org/10.1016/j.ejmg.2011.11.002DOI Listing
February 2012

Blepharophimosis mental retardation syndrome Say-Barber/Biesecker/Young-Simpson type - new findings with neuroimaging.

Am J Med Genet A 2011 Mar 22;155A(3):634-7. Epub 2011 Feb 22.

Institute of Pediatrics, Clinical Genetics Center, University of Debrecen, Hungary.

We report on a female patient with blepharophimosis mental retardation syndrome of Say/Barber/Biesecker/Young-Simpson (SBBYS) type. Main findings in her were marked developmental delay, blepharophimosis, ptosis, cleft palate, external auditory canal stenosis, small and malformed teeth, hypothyroidism, hearing impairment, and joint limitations. We performed diffusion tensor magnetic resonance imaging (MRI) and tractography of the brain which showed inappropriate myelination and disturbed white matter integrity. Cytogenetic analysis, subtelomeric fluorescence in situ hybridization and comparative genomic hybridization failed to identify an abnormality. It remains uncertain whether the MRI findings are specific to the present patient or form part of the SBBYS syndrome.
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http://dx.doi.org/10.1002/ajmg.a.33837DOI Listing
March 2011

Aiming at multidisciplinary consensus: what should be detected in prenatal diagnosis?

Prenat Diagn 2010 Nov;30(11):1049-56

Department of Obstetrics and Gynaecology, Academic Medical Center, Amsterdam, The Netherlands.

Objective: To determine expert consensus on which chromosomal abnormalities should and should not be detected in prenatal diagnosis, and for which abnormalities disagreement remains after structured discussion.

Methods: An expert panel of 24 prenatal experts (8 clinical cytogeneticists, 8 clinical geneticists and 8 obstetricians) rated 15 chromosomal abnormalities sampled from a nationwide study on rapid aneuploidy detection (RAD). In two individual anonymous rating rounds and one group meeting, the participants rated PRO or AGAINST detection and stated their main argument. The 15 chromosomal abnormalities were described in detail by a stylized vignette containing an obstetrical history, the indication for prenatal diagnosis and the range of possible outcomes of the chromosomal abnormality. Consensus was defined to be present if at least 80% of the experts agreed.

Results: Consensus was reached in 12 out of 15 cases. In ten cases, there was agreement PRO detection and in two cases experts agreed AGAINST detection. At the end of the third round, dissensus remained on three abnormalities.

Conclusion: Experts largely agreed on detecting chromosomal abnormalities with severe consequences and AGAINST detection in case of irrelevant clinical consequences. For chromosomal abnormalities with mild or uncertain outcomes, dissensus remained. None of the currently available tests corresponds to these demands.
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http://dx.doi.org/10.1002/pd.2609DOI Listing
November 2010

Selective chromosome analysis in couples with two or more miscarriages: case-control study.

BMJ 2005 Jul 28;331(7509):137-41. Epub 2005 Jun 28.

Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Academic Medical Centre, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, Netherlands.

Objective: To identify additional factors, such as maternal age or factors related to previous reproductive outcome or family history, and the corresponding probability of carrying a chromosome abnormality in couples with two or more miscarriages.

Design: Nested case-control study.

Setting: Six centres for clinical genetics in the Netherlands.

Participants: Couples referred for chromosome analysis after two or more miscarriages in 1992-2000; 279 carrier couples were marked as cases, and 428 non-carrier couples served as controls.

Main Outcome Measures: Independent factors influencing the probability of carrier status and the corresponding probability of carrier status.

Results: Four factors influencing the probability of carrier status could be identified: maternal age at second miscarriage, a history of three or more miscarriages, a history of two or more miscarriages in a brother or sister of either partner, and a history of two or more miscarriages in the parents of either partner. The calculated probability of carrier status in couples referred for chromosome analysis after two or more miscarriages varied between 0.5% and 10.2%.

Conclusions: The probability of carrier status in couples with two or more miscarriages is modified by additional factors. Selective chromosome analysis would result in a more appropriate referral policy, could decrease the annual number of chromosome analyses, and could therefore lower the costs.
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http://dx.doi.org/10.1136/bmj.38498.669595.8FDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC558698PMC
July 2005

Trisomy 13 or 18 (mosaicism) in first trimester cytotrophoblast cells: false-positive results in 11 out of 51 cases.

Eur J Obstet Gynecol Reprod Biol 2002 Mar;101(2):161-8

Department of Clinical Genetics, Academic Medical Centre, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands.

Objective: The finding of full or mosaic trisomy 13 or 18 in first trimester chorionic villus sampling (CVS) may be a false-positive result. This report provides incidence and outcome information that may be helpful in counselling individual patients and in choosing adequate follow-up.

Study Design: From a series of 6820 CVS cases, we retrospectively collected data on all patients (n=51) with full (n=30) or mosaic (n=5) trisomy 18, and full (n=13) or mosaic (n=3) trisomy 13 in cytotrophoblast cells.

Results: Five false-positives were seen in patients with full trisomy 18 and three in the mosaic cases. One false-positive result was observed in full trisomy 13 and two false-positives in cases of mosaicism. No false-negative results were reported.

Conclusion: The diagnosis of trisomy 13 or 18 in cytotrophoblasts should be confirmed in other tissues, unless fetal abnormalities are seen at ultrasound. In case of mosaicism, follow-up amniocentesis is advised.
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http://dx.doi.org/10.1016/s0301-2115(00)00542-xDOI Listing
March 2002