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

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.

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Prenatal Diagnosis of a 2.5 Mb De Novo 17q24.1q24.2 Deletion Encompassing KPNA2 and PSMD12 Genes in a Fetus with Craniofacial Dysmorphism, Equinovarus Feet, and Syndactyly

Case Reports in Genetics ◽

10.1155/2017/7803136 ◽

2017 ◽

Vol 2017 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Marie-Emmanuelle Naud ◽

Lucie Tosca ◽

Jelena Martinovic ◽

Julien Saada ◽

Corinne Métay ◽

...

Keyword(s):

Intellectual Disability ◽

Prenatal Diagnosis ◽

De Novo ◽

Chromosomal Microarray ◽

Facial Dysmorphism ◽

Chromosomal Microarray Analysis ◽

Conventional Cytogenetic Analysis ◽

First Case ◽

Craniofacial Dysmorphism ◽

Talipes Equinovarus

Interstitial 17q24.1 or 17q24.2 deletions were reported after conventional cytogenetic analysis or chromosomal microarray analysis in patients presenting intellectual disability, facial dysmorphism, and/or malformations. We report on a fetus with craniofacial dysmorphism, talipes equinovarus, and syndactyly associated with a de novo 2.5 Mb 17q24.1q24.2 deletion. Among the deleted genes, KPNA2 and PSMD12 are discussed for the correlation with the fetal phenotype. This is the first case of prenatal diagnosis of 17q24.1q24.2 deletion.

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A Recurrent De Novo Terminal Duplication of 14q32 in Korean Siblings Associated with Developmental Delay and Intellectual Disability, Growth Retardation, Facial Dysmorphism, and Cerebral Infarction: A Case Report and Literature Review

Genes ◽

10.3390/genes12091388 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1388

Author(s):

Jiyoon Han ◽

Joonhong Park

Keyword(s):

Intellectual Disability ◽

Cerebral Infarction ◽

Exome Sequencing ◽

Developmental Delay ◽

Growth Retardation ◽

De Novo ◽

Confirmatory Test ◽

Chromosomal Microarray ◽

Facial Dysmorphism ◽

Coverage Analysis

The terminal 14q32 duplication has been reported often in association with other cytogenetic abnormalities, and individuals with this specific duplication showed varying degrees of developmental delay/intellectual disability (DD/ID) and growth retardation (GR), and distinct facial dysmorphisms. Herein, based on the limited cases of terminal duplication of 14q32 known to date, we present new affected siblings presenting with DD/ID, GR, and facial dysmorphism, as well as cerebral infarction caused by recurrent de novo der(14)t(14;14)(p11.2;q32.1) leading to terminal duplication of 14q32. We used coverage analysis generated via duo exome sequencing, performed chromosomal microarray (CMA) as a confirmatory test, and compared our findings with those reported previously. Coverage analysis generated via duo exome sequencing revealed a 17.2 Mb heterozygous duplication at chromosome 14q32.11-q32.33 with a Z ratio ranging between 0.5 and 1 in the proband and her elder brother. As a complementary method, CMA established a terminal duplication described as the arr[hg19]14q32.11q32.33(90,043,558_107,258,824)x3 in the proband and her elder brother; however, the parents and other siblings showed normal karyotyping and no abnormal gain or loss of CMA results. Five candidate genes, BCL11B, CCNK, YY1, DYNC1H1, and PACS2, were associated with the clinical phenotypes in our cases. Although the parents had normal chromosomes, two affected cases carrying terminal duplication of 14q32 can be explained by gonadal mosaicism. Further studies are needed to establish the association between cerebrovascular events and terminal duplication of chromosome 14q32, including investigation into the cytogenetics of patients with precise clinical descriptions.

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Two-Generation Transmission of Trisomy 18p: Prenatal Diagnosis in a Woman with Mild Intellectual Disability

Cytogenetic and Genome Research ◽

10.1159/000499173 ◽

2019 ◽

Vol 157 (4) ◽

pp. 220-226

Author(s):

Yang Yu ◽

Yuting Jiang ◽

Xiaonan Hu ◽

Hongguo Zhang ◽

Ruizhi Liu ◽

...

Keyword(s):

Intellectual Disability ◽

Prenatal Diagnosis ◽

Prenatal Testing ◽

Unknown Origin ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Chromosome 15 ◽

Derivative Chromosome ◽

Mild Intellectual Disability ◽

Trisomy 18P

Trisomy 18p is a rarely observed chromosomal aberration. Only 31 cases have previously been described in the literature. Trisomy 18p is associated with mild to moderate phenotypic anomalies and intellectual disability. Here, we report on a pregnant woman in whom noninvasive prenatal testing indicated a high risk of fetal trisomy 18. Prenatal diagnosis and karyotyping of the parents were performed and demonstrated that both the mother and the fetus had a derivative chromosome 15 with a segment of unknown origin. Chromosomal microarray analysis and FISH revealed a 14.9-Mb duplication of 18p and detected 3 centromeres of chromosome 18. To our knowledge, this is the first study reporting trisomy 18p due to an unbalanced translocation of 18p onto chromosome 15q showing 2-generation transmission. The results suggest that trisomy 18p can be considered a euchromatic variant.

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Duplication of 19p13.3 in 11-Year-Old Male Patient with Dysmorphic Features and Intellectual Disability: A Review

Journal of Pediatric Genetics ◽

10.1055/s-0037-1603650 ◽

2017 ◽

Vol 06 (04) ◽

pp. 227-233 ◽

Cited By ~ 2

Author(s):

Irina Novikova ◽

Paushpala Sen ◽

Ann Manzardo ◽

Merlin Butler

Keyword(s):

Intellectual Disability ◽

Male Patient ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Clinical Report ◽

Intrauterine Growth ◽

Interstitial Duplication ◽

Craniofacial Features ◽

Sparse Hair ◽

Small Mouth

AbstractWe present a clinical report of an 11-year-old male patient with an interstitial duplication of 19p13.3 (829 kb in size) at genomic coordinates 3,804,495–4,033,722 bp (hg19) identified by chromosomal microarray analysis and review the literature from nine published reports adding knowledge regarding this chromosomal anomaly and clinical outcomes. The size of the duplication ranged from 0.83 to 8.9 Mb in the nine individuals. The young boy in our report was dysmorphic with microcephaly, abnormal craniofacial features, intellectual disability, aggression, and a heart murmur. All patients were found to have a psychomotor developmental delay and/or intellectual disability with the majority having microcephaly, intrauterine growth retardation, and hypotonia. Common craniofacial findings included a tall, prominent forehead, an elongated face, epicanthal folds, hypertelorism, prominent low-set ears, philtrum anomaly, and a small mouth. Other less common features included abnormal digits, sparse hair, and cardiac defects. Clinical features, chromosome duplication sizes, locations, and the number of genes will be summarized in a tabular form.

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

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2018-0439 ◽

2019 ◽

Vol 32 (7) ◽

pp. 667-674 ◽

Cited By ~ 1

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.

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Cost Effectiveness of Karyotyping, Chromosomal Microarray Analysis, and Targeted Next-Generation Sequencing of Patients with Unexplained Global Developmental Delay or Intellectual Disability

Molecular Diagnosis & Therapy ◽

10.1007/s40291-017-0309-5 ◽

2017 ◽

Vol 22 (1) ◽

pp. 129-138 ◽

Cited By ~ 6

Author(s):

Yonghong Li ◽

Lori A. Anderson ◽

Edward I. Ginns ◽

James J. Devlin

Keyword(s):

Intellectual Disability ◽

Cost Effectiveness ◽

Next Generation Sequencing ◽

Developmental Delay ◽

Microarray Analysis ◽

Chromosomal Microarray ◽

Global Developmental Delay ◽

Chromosomal Microarray Analysis ◽

Targeted Next Generation Sequencing ◽

Generation Sequencing

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A non-syndromic intellectual disability associated with a de novo microdeletion at 7q and 18p, microduplication at Xp, and 18q partial trisomy detected using chromosomal microarray analysis approach

Molecular Cytogenetics ◽

10.1186/1755-8166-7-44 ◽

2014 ◽

Vol 7 (1) ◽

pp. 44 ◽

Cited By ~ 6

Author(s):

Irene Pinto ◽

Lysa Minasi ◽

Alex da Cruz ◽

Aldaires de Melo ◽

Damiana da Cruz e Cunha ◽

...

Keyword(s):

Intellectual Disability ◽

Microarray Analysis ◽

De Novo ◽

Partial Trisomy ◽

Analysis Approach ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis

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Prenatal diagnosis of HNF1B-associated renal cysts: Need to differentiate intragenic variants from 17q12 microdeletion syndrome?

10.1101/576918 ◽

2019 ◽

Author(s):

Georgia Vasileiou ◽

Juliane Hoyer ◽

Christian T. Thiel ◽

Jan Schaefer ◽

Maren Zapke ◽

...

Keyword(s):

Clinical Features ◽

Spatial Clustering ◽

Renal Cysts ◽

Computational Prediction ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Renal Anomalies ◽

Systematic Classification ◽

Cystic Kidneys ◽

Large Deletions

ABSTRACTObjectiveLarge deletions of chromosome 17q12 (17q12DS) or intragenic variants in HNF1B are associated with variable developmental, endocrine and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe pre- and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to previous studies.MethodsPrenatal sequencing and postnatal chromosomal microarray analysis was performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants.ResultsIn a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA binding domain, a mutational hotspot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions of varying size. Literature screening revealed highly variable reporting of HNF1B-associated clinical traits. Overall, developmental delay was more frequent in 17q12DS carriers, although both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum.ConclusionsWe highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants is necessary for a more accurate risk quantification of pre- and postnatal clinical features, improving genetic counseling and prenatal decision-making.

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Outcomes of pregnancies with trisomy 16 mosaicism detected by NIPT: a series of case reports

Molecular Cytogenetics ◽

10.1186/s13039-021-00559-w ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Haishan Peng ◽

Jiexia Yang ◽

Dongmei Wang ◽

Fangfang Guo ◽

Yaping Hou ◽

...

Keyword(s):

Prenatal Diagnosis ◽

High Risk ◽

False Positive ◽

Case Reports ◽

Screening Method ◽

Prenatal Testing ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

True Positive ◽

Trisomy 16

Abstract Background Trisomy 16 (T16) is thought to be the most frequent chromosome abnormality at conception, which is often associated with a high risk of abnormal outcomes. Methods A retrospective analysis of 14 cases with high risk of T16 by noninvasive prenatal testing (NIPT) was conducted. All cases in the analysis involved prenatal diagnosis, karyotyping and chromosomal microarray analysis. Case reports NIPT detected 12 cases of T16 and 2 cases of T16 mosaicism. Prenatal diagnosis confirmed 5 true positive cases and 9 false positive cases. Among the 5 true positive cases, 3 cases had ultrasound abnormalities. All of the 9 false positive cases continued their pregnancies. The newborns who were from these 9 false positive cases except 1 case (case 7) had low birth weights (< 2.5 kg) and there were also 2 premature deliveries. Conclusion NIPT serves as a fast and early prenatal screening method, giving clues to chromosome abnormalities and providing guidance for managing pregnancy. Confined placental mosaicism in 16 pregnancies may be at higher risk for preterm delivery.

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