First Report of Low-Rate Mosaicism for 20q11.21q12 Deletion and Delineation of the Associated Disorder

2018 ◽  
Vol 156 (2) ◽  
pp. 87-94
Author(s):  
Sara Loddo ◽  
Viola Alesi ◽  
Silvia Genovese ◽  
Valeria Orlando ◽  
Chiara Calacci ◽  
...  
Keyword(s):  
Growth Retardation ◽  
Snp Array ◽  
Small Region ◽  
Growth Delay ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Psychomotor Delay ◽  
Feeding Difficulties ◽  
First Case ◽  
Snp Array Analysis

Interstitial deletions of the long arm of chromosome 20 are very rare, with only 12 reported patients harboring the 20q11.2 microdeletion and presenting a disorder characterized by psychomotor and growth delay, dysmorphisms, and brachy-/clinodactyly. We describe the first case of mosaic 20q11.2 deletion in a 5-year-old girl affected by mild psychomotor delay, feeding difficulties, growth retardation, craniofacial dysmorphisms, and finger anomalies. SNP array analysis disclosed 20% of cells with a 20q11.21q12 deletion, encompassing the 20q11.2 minimal critical region and the 3 OMIM disease-causing genes GDF5, EPB41L1, and SAMHD1. We propose a pathogenic role of other genes mapping outside the small region of overlap, in particular GHRH (growth hormone releasing hormone), whose haploinsufficiency could be responsible for the prenatal onset of growth retardation which is shared by half of these patients. Our patient highlights the utility of chromosomal microarray analysis to identify low-level mosaicism.

scholarly journals Integrated CNV-seq, karyotyping and SNP-array analyses for effective prenatal diagnosis of chromosomal mosaicism

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Na Ma ◽  
Hui Xi ◽  
Jing Chen ◽  
Ying Peng ◽  
Zhengjun Jia ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Sex Chromosome ◽  
Snp Array ◽  
Genomic Rearrangements ◽  
Chromosomal Mosaicism ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Low Level ◽  
Autosomal Aneuploidy ◽  
Number Variation

Abstract Background Emerging studies suggest that low‐coverage massively parallel copy number variation sequencing (CNV-seq) more sensitive than chromosomal microarray analysis (CMA) for detecting low-level mosaicism. However, a retrospective back-to-back comparison evaluating accuracy, efficacy, and incremental yield of CNV-seq compared with CMA is warranted. Methods A total of 72 mosaicism cases identified by karyotyping or CMA were recruited to the study. There were 67 mosaic samples co-analysed by CMA and CNV-seq, comprising 40 with sex chromosome aneuploidy, 22 with autosomal aneuploidy and 5 with large cryptic genomic rearrangements. Results Of the 67 positive mosaic cases, the levels of mosaicism defined by CNV-seq ranged from 6 to 92% compared to the ratio from 3 to 90% by karyotyping and 20% to 72% by CMA. CNV-seq not only identified all 43 chromosomal aneuploidies or large cryptic genomic rearrangements detected by CMA, but also provided a 34.88% (15/43) increased yield compared with CMA. The improved yield of mosaicism detection by CNV-seq was largely due to the ability to detect low level mosaicism below 20%. Conclusion In the context of prenatal diagnosis, CNV-seq identified additional and clinically significant mosaicism with enhanced resolution and increased sensitivity. This study provides strong evidence for applying CNV-seq as an alternative to CMA for detection of aneuploidy and mosaic variants.

scholarly journals Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 588
Author(s):  
Pierpaola Tannorella ◽  
Daniele Minervino ◽  
Sara Guzzetti ◽  
Alessandro Vimercati ◽  
Luciano Calzari ◽  
...  
Keyword(s):  
Growth Retardation ◽  
Molecular Mechanisms ◽  
Uniparental Disomy ◽  
Postnatal Growth ◽  
Molecular Diagnostic ◽  
Growth Delay ◽  
Molecular Defect ◽  
Maternal Uniparental Disomy ◽  
Feeding Difficulties ◽  
Silver Russell Syndrome

Silver Russell Syndrome (SRS, MIM #180860) is a rare growth retardation disorder in which clinical diagnosis is based on six features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine–Harbison clinical scoring system (NH-CSS)). The molecular mechanisms consist in (epi)genetic deregulations at multiple loci: the loss of methylation (LOM) at the paternal H19/IGF2:IG-DMR (chr11p15.5) (50%) and the maternal uniparental disomy of chromosome 7 (UPD(7)mat) (10%) are the most frequent causes. Thus far, about 40% of SRS remains undiagnosed, pointing to the need to define the rare mechanisms in such a consistent fraction of unsolved patients. Within a cohort of 176 SRS with an NH-CSS ≥ 3, a molecular diagnosis was disclosed in about 45%. Among the remaining patients, we identified in 3 probands (1.7%) with UPD(20)mat (Mulchandani–Bhoj–Conlin syndrome, OMIM #617352), a molecular mechanism deregulating the GNAS locus and described in 21 cases, characterized by severe feeding difficulties associated with failure to thrive, preterm birth, and intrauterine/postnatal growth retardation. Our patients share prominent forehead, feeding difficulties, postnatal growth delay, and advanced maternal age. Their clinical assessment and molecular diagnostic flowchart contribute to better define the characteristics of this rare imprinting disorder and to rank UPD(20)mat as the fourth most common pathogenic molecular defect causative of SRS.

Genomic study via chromosomal microarray analysis in a group of Romanian patients with obesity and developmental disability/intellectual disability

2019 ◽  
Vol 32 (7) ◽  
pp. 667-674 ◽  
Author(s):  
Diana Micleaa ◽  
Camelia Al-Khzouza ◽  
Sergiu Osan ◽  
Simona Bucerzan ◽  
Victoria Cret ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Disability ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Genomic Analysis ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Syndromic Obesity ◽  
Genomic Study ◽  
Array Technology

Abstract Background Obesity with developmental disability/intellectual disability (DD/ID) is the most common association in syndromic obesity. Genomic analysis studies have allowed the decipherment of disease aetiology, both in cases of syndromic obesity as well as in cases of isolated or syndromic DD/ID. However, more data are needed to further elucidate the link between the two. The aim of this pangenomic study was to use single nucleotide polymorphism (SNP) array technology to determine the copy number variant (CNV) type and frequency associated with both obesity and DD/ID. Methods Thirty-six patients were recruited from the Clinical Emergency Hospital for Children, in Cluj-Napoca, Romania during the period 2015–2017. The main inclusion criterion was a diagnosis that included both obesity and DD/ID. Genomic analysis via SNP array technology was performed. Results Out of the 36 patients, 12 (33%) presented CNVs with a higher degree of pathogenicity (A group) and 24 (66%) presented benign CNVs (B group). The SNP array results for the A group were as follows: pathogenic CNVs in 8/12 patients (67%); variants of unknown significance (VOUS) in 2/12 patients (16%); and uniparental disomy (UPD) in 2/12 patients (16%). Conclusions Some of these CNVs have already been observed in patients with both obesity and DD/ID, but the others were noticed only in DD/ID patients and have not been described until now in association with obesity.

scholarly journals Interpreting Discordant Monosomy 3 FISH and Chromosomal Microarray Analysis Results in Uveal Melanoma

2020 ◽  
Author(s):  
Nicholas Coley ◽  
Christopher Long ◽  
Simrin Sennik ◽  
John Thorson ◽  
Jonathan Lin
Keyword(s):  
Microarray Analysis ◽  
Uveal Melanoma ◽  
Molecular Pathology ◽  
Limit Of Detection ◽  
Prognostic Indicators ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
First Case ◽  
Monosomy 3 ◽  
Single Positive

Abstract Background: Uveal melanoma is the most common primary ocular tumor in adults and causes morbidity through lymphovascular metastasis. The presence of monosomy 3 in uveal melanomas is one of the most important prognostic indicators for metastasis. Two major molecular pathology testing modalities to assess monosomy 3 are fluorescent in situ hybridization (FISH) and chromosomal microarray analysis (CMA). Here, we report two cases of discordant monosomy 3 test results in uveal melanoma enucleation specimens using these molecular pathology tests.Case presentation: The first case is a uveal melanoma from a 51-year-old male that showed no evidence of monosomy 3 by CMA, but was subsequently detected by FISH. The second case is a uveal melanoma from a 49-year-old male that showed monosomy 3 at the limit of detection by CMA that was not detected by subsequent FISH.Conclusions: These two cases underscore the differences of each testing modality for monosomy 3. The high percentage of cells with one chromosome 3 signal requisite for a positive monosomy 3 FISH result may not be sensitive enough to detect a low level of monosomy 3 that CMA can detect. Conversely, a small uveal melanoma with monosomy 3 may be missed by CMA owing to background DNA from cytologically normal retina and other ocular tissues. Our cases suggest that both testing methods should be pursued for uveal melanoma, with a single positive result for either test interpreted as presence of monosomy 3.

Rapid Diagnosis of Imprinting Disorders Involving Copy Number Variation and Uniparental Disomy Using Genome-Wide SNP Microarrays

2015 ◽  
Vol 146 (1) ◽  
pp. 9-18 ◽  
Author(s):  
Weiqiang Liu ◽  
Rui Zhang ◽  
Jun Wei ◽  
Huimin Zhang ◽  
Guojiu Yu ◽  
...  
Keyword(s):  
Copy Number ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Copy Number Variations ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Imprinting Disorders ◽  
Genome Wide ◽  
Number Variation ◽  
Efficient Alternative

Imprinting disorders, such as Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS) and Angelman syndrome (AS), can be detected via methylation analysis, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), or other methods. In this study, we applied single nucleotide polymorphism (SNP)-based chromosomal microarray analysis to detect copy number variations (CNVs) and uniparental disomy (UPD) events in patients with suspected imprinting disorders. Of 4 patients, 2 had a 5.25-Mb microdeletion in the 15q11.2q13.2 region, 1 had a 38.4-Mb mosaic UPD in the 11p15.4 region, and 1 had a 60-Mb detectable UPD between regions 14q13.2 and 14q32.13. Although the 14q32.2 region was classified as normal by SNP array for the 14q13 UPD patient, it turned out to be a heterodisomic UPD by short tandem repeat marker analysis. MS-MLPA analysis was performed to validate the variations. In conclusion, SNP-based microarray is an efficient alternative method for quickly and precisely diagnosing PWS, AS, BWS, and other imprinted gene-associated disorders when considering aberrations due to CNVs and most types of UPD.

scholarly journals Prenatal diagnosis of cri-du-chat syndrome by SNP array: report of twelve cases and review of the literature

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiasun Su ◽  
Huayu Fu ◽  
Bobo Xie ◽  
Weiliang Lu ◽  
Wei Li ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Snp Array ◽  
Nasal Bone ◽  
Hydrops Fetalis ◽  
Terminal Deletion ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Cri Du Chat Syndrome ◽  
Definitive Method ◽  
Hypoplastic Nasal Bone

Abstract Background Cri-du-chat syndrome (CdCS; OMIM#123450) is a classic contiguous gene syndrome caused by chromosome 5p terminal deletion (5p-), which characterized by a high-pitched cat-like cry, developmental delay, severe psychomotor, mental retardation, and dysmorphic features in infancy. Prenatal diagnosis of CdCS is difficult due to the non-specific ultrasound features. And reports using array analysis are rare. This study presented the first retrospective analysis of prenatal series of CdCS fetuses diagnosed by single nucleotide polymorphism (SNP) array in China. Case presentation A total of 35,233 pregnant women were enrolled from Jan 2014 to April 2019 in our center, there are twelve 5p- cases with abnormal sonographic signs revealed by SNP array, giving an incidence of 0.034% (12/35,233). Clinical information and molecular basis included: maternal demographics, indications for invasive testing, sonographic findings and SNP array results. Among all the 5p- cases revealed, nine cases were diagnosed by both karyotyping and SNP array, three cases were detected only by SNP array. Half of our cases (6/12) had an isolated 5p terminal deletion, which sizes ranged from 9.0 Mb to 30 Mb. The other half of cases (6/12) characterized by unbalanced translocation, with sex ratio 7:5 (female: male), when combine the clinical features observed from this study and available literature, the most frequent anomaly observed in prenatal ultrasound examination of CdCS was cerebral abnormalities, accounted for 44.4% (16/36) of the existing cases. Features that are less consistent included: choroid plexus cyst (13.8%, 5/36), single umbilical artery (13.3%, 4/30), ventricular septal defect (11.1%, 4/36), hydrops fetalis (8.3%, 3/36), ascites (8.3%, 3/36), increased NT/NF (8.3%, 3/36), absent/severely hypoplastic nasal bone (5.5%, 2/36), in order. Conclusion Prenatal findings such as cerebral abnormalities, absent/hypoplastic nasal bone, hydrops fetalis, ascites or encephalocele may act as suggestive signs of CdCS or other microdeletion/duplication syndromes. Combining typical karyotyping with chromosomal microarray analysis (CMA) is a definitive method for a precise diagnosis of CdCS and provides more accurate results in order to offer genetic counseling to families which need to deal with cryptic aberrations.

scholarly journals First Case Report of Maternal Mosaic Tetrasomy 9p Incidentally Detected on Non-Invasive Prenatal Testing

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 370
Author(s):  
Wendy Shu ◽  
Shirley S. W. Cheng ◽  
Shuwen Xue ◽  
Lin Wai Chan ◽  
Sung Inda Soong ◽  
...  
Keyword(s):  
Chromosomal Aberrations ◽  
Prenatal Testing ◽  
Current Approach ◽  
Chromosomal Microarray ◽  
Genetic Syndrome ◽  
Psychomotor Delay ◽  
Non Invasive ◽  
First Case ◽  
Chromosome 9P ◽  
Copy Number Changes

Tetrasomy 9p (ORPHA:3390) is a rare syndrome, hallmarked by growth retardation; psychomotor delay; mild to moderate intellectual disability; and a spectrum of skeletal, cardiac, renal and urogenital defects. Here we present a Chinese female with good past health who conceived her pregnancy naturally. Non-invasive prenatal testing (NIPT) showed multiple chromosomal aberrations were consistently detected in two sampling times, which included elevation in DNA from chromosome 9p. Amniocentesis was performed and sent for chromosomal microarray, which was normal. Maternal karyotype revealed that mos 47,XX,+dic(9;9)(q21.1;q21.1)(24)/46,XX(9) presents mosaic tetrasomy for the short arm of chromosome 9p and is related to the NIPT results showing elevation in DNA from chromosome 9p. The pregnancy was uneventful, and the patient was delivered at term. Maternal samples were obtained at two different time points after delivery showed the same multiple chromosomal aberrations detected during pregnancy. This is a first report on an unusual case of mosaic isodicentric tetrasomy 9p in a healthy adult with normal intellect. With widespread adoption of NIPT for screening fetal aneuploidy and genome-wide copy number changes, a rise in incidental detection of maternal rare genetic syndrome will bring challenges in our current approach to genetic counselling and prenatal diagnosis.

scholarly journals Wolf-Hirschhorn Syndrome: Clinical and Genetic Study of 7 New Cases, and Mini Review

Children ◽  
2021 ◽  
Vol 8 (9) ◽  
pp. 751
Author(s):  
Eva-Cristiana Gavril ◽  
Alina Costina Luca ◽  
Alexandrina-Stefania Curpan ◽  
Roxana Popescu ◽  
Irina Resmerita ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Growth Retardation ◽  
Screening Method ◽  
Postnatal Growth ◽  
Chromosomal Microarray ◽  
Clinical Aspects ◽  
Facial Dysmorphism ◽  
Chromosomal Microarray Analysis ◽  
Renal Anomalies ◽  
Craniofacial Dysmorphism

Wolf–Hirschhorn syndrome (WHS), a rare disorder determined by distal 4p deletion, is characterized by a pre and postnatal growth retardation, hypotonia, intellectual disability, epilepsy, craniofacial dysmorphism, and congenital fusion anomalies. The clinical aspects are dependent on the deletion’ size. Our aim was to identify rare specific characteristics in a cohort of seven cases with 4p deletion and to assess the utility of Multiplex ligation-dependent probe amplification (MLPA) (cheap and sensitive test)—combined kits—as a diagnostic test and selection tool for cases that require other investigations (chromosomal microarray analysis—CMA, karyotype). For all cases we conducted a clinical examination with the main features identified: facial dysmorphism, intellectual disability, postnatal development delay, cardiac defects and hypotonia. In some cases, we observed seizures, structural brain abnormalities, immunodeficiencies, and renal anomalies. Prenatal growth retardation was detected in a relatively small number of cases, but postnatal growth failure was a constant feature. In all cases, the clinical diagnosis was confirmed by genetic analyses: karyotype and/or MLPA. In conclusion, renal and brain defects, as well as immunodeficiency are rare manifestations and should be looked for. Although CMA is the standard test, in our experience, MLPA is also a reliable screening method as the identified cases were either confirmed by MLPA or selected for further investigations.

Clinical and molecular-genetics diagnosis of microdeletion Xp11.4

2020 ◽  
pp. 35-36
Author(s):  
М.Е. Миньженкова ◽  
Ж.Г. Маркова ◽  
Т.В. Маркова ◽  
Н.В. Шилова
Keyword(s):  
Molecular Genetic ◽  
Clinical Manifestations ◽  
Speech Development ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Cerebellar Hypoplasia ◽  
Pontocerebellar Hypoplasia ◽  
Molecular Genetic Study ◽  
Psychomotor Delay ◽  
Study Results

Представлены клинические и молекулярно-генетические результаты обследования девочки с задержкой психомоторного, речевого и физического развития, микроцефалией, гипоплазией моста и мозжечка. Хромосомный микроматричный анализ позволил выявить делецию Хр11.4, затрагивающую ген CASK, который ассоциирован с клиническими проявлениями MICPCH-синдрома (mental retardation and microcephaly with pontine and cerebellar hypoplasia). Сlinical and molecular-genetic study results of a girl with developemental and psychomotor delay, lack of speech development, microcephaly, and pontocerebellar hypoplasia are presented. Chromosomal microarray analysis revealed a deletion of Xp11.4 affecting the CASK gene that is associated with clinical manifestations of MICPCH-syndrome.

scholarly journals Deletion of 16q22.2q23.3 in a Boy with a Phenotype Reminiscent of Silver-Russell Syndrome

2021 ◽  
pp. 1-5
Author(s):  
Anna Lengyel ◽  
Éva Pinti ◽  
Thomas Eggermann ◽  
György Fekete ◽  
Irén Haltrich
Keyword(s):  
Snp Array ◽  
Large Deletion ◽  
Global Developmental Delay ◽  
Array Analysis ◽  
Triangular Face ◽  
Feeding Difficulties ◽  
Wide Variability ◽  
Snp Array Analysis ◽  
Minor Anomalies ◽  
Silver Russell Syndrome

A 15-month-old boy presented with growth and global developmental delay, feeding difficulties, sleep disturbance and several minor anomalies, including a large anterior fontanel, relative macrocephaly, and a triangular face. Clinical suspicion prompted genetic investigations for Silver-Russell syndrome and related disorders. SNP array analysis led to the diagnosis of an approximately 10-Mb large deletion of the long arm in chromosome 16q22.2q23.3. Interstitial deletions of 16q show a wide variability of related features; however, considering the differences in size and location of the deletions in the known patients, the phenotypic overlap is surprising. Here, we report a novel microdeletion, compare the proband with data from scientific literature and international databases, and discuss possible diagnostic implications.

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