Unusual Duplication in the Pericentromeric Region of Chromosome 9 in a Patient with Phenotypic Alterations

Several alterations involving the pericentromeric region of chromosome 9 are considered as normal population variants. These heterochromatic variants or heteromorphisms can include 9qh+, 9cen+, 9ph+, 9ph-, inv(9)(p11q13), and other patterns which can only be defined by FISH studies. However, some heteromorphisms have been found more frequently in patients with several clinical disorders. Here, we report on a patient with intellectual disability, language and neurodevelopmental delay, as well as facial dysmorphism and an unusual chromosome 9. While the banding karyotype was indicative of a simple pericentric inversion of one chromosome 9 [46,XX,inv(9)(p12q13)], array comparative genomic hybridization showed a 6-Mb duplication, including 22 genes: arr[hg19] 9p13.1p11.2(38,869,901- 44,870,714)×3 dn. Molecular cytogenetics using a panel of probes specific for the pericentromeric region of chromosome 9 showed an unusual, rearranged chromosome 9, der(9)(pter→p11.2::q21.11→q12::p11.2→p13.2::q12→p11.2::q21.11→qter), that has not been described before. The patient's phenotypic alterations are probably due to the de novo 6-Mb 9p duplication, although a review of similar cases showed some reports considering this duplication in the euchromatic region as a benign variant. Interestingly, this is the first report of a possible adverse inversion loop formation due to a known heteromorphic pericentric inversion present in the phenotypically normal father of the patient.

Download Full-text

Analysis of the clinical features of pericentric inversion of chromosome 9

Journal of International Medical Research ◽

10.1177/0300060520957820 ◽

2020 ◽

Vol 48 (9) ◽

pp. 030006052095782

Author(s):

Xiaolei Xie ◽

Fuguang Li ◽

Weihe Tan ◽

Jiang Tang

Keyword(s):

Amniotic Fluid ◽

Clinical Features ◽

Pregnancy Outcomes ◽

Pericentric Inversion ◽

Adverse Pregnancy Outcome ◽

Normal Population ◽

Chorionic Villus ◽

Clinical Impact ◽

Chromosome 9 ◽

Adverse Pregnancy

Objective The pericentric inversion of chromosome 9 (inv9) is one of the most common structural balanced chromosomal variations, and it is considered to be a normal population variant. The aim of this study was to re-evaluate the clinical impact of patients with inv9. Methods We studied the karyotypes from 4853 patients at a single center and retrospectively reviewed their clinical data. Results There were 67 inv9 patients among 2988 adults, and 62 of them showed different clinical features, including male and female infertility, oligoasthenozoospermia, and azoospermia. Thirty-one cases of inv9 were found in 1865 fetuses, including two cases in chorionic villus (6.90%) and 29 in amniotic fluid (1.67%), but there were no cases in umbilical cord blood. The rates of fetal phenotype abnormal and adverse pregnancy outcome with inv9 in the chorionic villus were 100.00% (2/2), while only 17.24% (5/29) in the amniotic fluid showed abnormalities, among which 60.00% (3/5) had adverse pregnancy outcomes. Conclusions Although there is no clear evidence that inv9 is pathogenic, the genetic counseling on inv9 in early pregnancy and adults needs to be given more attention.

Download Full-text

Cerebral White Matter Lesions and Dysmorphisms: Signs Suggestive of 6p25 Deletion Syndrome—Literature Review

Journal of Pediatric Genetics ◽

10.1055/s-0039-1694015 ◽

2019 ◽

Vol 08 (04) ◽

pp. 205-211

Author(s):

Piero Pavone ◽

Simona Domenica Marino ◽

Giovanni Corsello ◽

Martino Ruggieri ◽

Danilo Castellano Chiodo ◽

...

Keyword(s):

White Matter ◽

Developmental Delay ◽

De Novo ◽

Clinical Manifestations ◽

Deletion Syndrome ◽

Cerebral White Matter ◽

Comparative Genomic ◽

Facial Dysmorphism ◽

Perivascular Spaces ◽

Renal Malformations

AbstractDeletion of the region including chromosome 6p25 has been defined as a syndrome, with more than 68 reported cases. Individuals affected by the syndrome exhibit variable findings, including developmental delay and intellectual disability, cardiac anomalies, dysmorphic features, and—less commonly—skeletal and renal malformations. Ocular and hearing abnormalities are the most notable presenting features. The region encompasses more than 15 genes, of which the FOX group is the most likely causal factor of the clinical manifestations. We report the case of a 2-year-old child with developmental delay, generalized hypotonia, facial dysmorphism, and anomalies involving malformations of the eyes, heart, teeth, and skeleton. The magnetic resonance imaging (MRI) of the child's brain displayed cerebral anomalies involving the white matter, perivascular spaces, and corpus callosum. Array-CGH (comparative genomic hybridization) analysis displayed a de novo partial deletion of the short arm of chromosome 6, extending 5.13 Mb from nt 407.231 to nt 5.541.179. In infancy, neuroradiologic findings of abnormalities in the cerebral white matter and other neurologic anomalies elsewhere in the brain, in association with dysmorphisms and malformations, are highly suggestive of the diagnosis of 6p25 deletion syndrome. When these anomalies are found, the syndrome must be included in the differential diagnosis of disorders affecting the cerebral white matter.

Download Full-text

Significance Analysis of Microarrays (SAM) Offers Clues to Differences between the Genomes of Adult Philadelphia Positive ALL and the Lymphoid Blast Transformation of CML

Cancer Informatics ◽

10.4137/cin.s9258 ◽

2012 ◽

Vol 11 ◽

pp. CIN.S9258 ◽

Cited By ~ 10

Author(s):

Colin Grace ◽

Elisabeth P. Nacheva

Keyword(s):

De Novo ◽

Blast Crisis ◽

Chronic Phase ◽

Chromosome 9 ◽

Comparative Genomic ◽

Blast Transformation ◽

Significance Analysis ◽

Genome Data ◽

Genome Screening ◽

Blast Cells

Philadelphia positive malignant disorders are a clinically divergent group of leukemias. These include chronic myeloid leukemia (CML) and de novo acute Philadelphia positive (Ph(+)) leukemia of both myeloid, and lymphoid origin. Recent whole genome screening of Ph(+)ALL in both children and adults identified an almost obligatory cryptic loss of Ikaros, required for the normal B cell maturation. Although similar losses were found in lymphoid blast crisis the genetic background of the transformation in CML is still poorly defined. We used Significance Analysis of Microarrays (SAM) to analyze comparative genomic hybridization (aCGH) data from 30 CML (10 each of chronic phase, myeloid and lymphoid blast stage), 10 Ph(+)ALL adult patients and 10 disease free controls and were able to: (a) discriminate between the genomes of lymphoid and myeloid blast cells and (b) identify differences in the genome profile of de novo Ph(+)ALL and lymphoid blast transformation of CML (BC/L). Furthermore we were able to distinguish a sub group of Ph(+) ALL characterized by gains in chromosome 9 and recurrent losses at several other genome sites offering genetic evidence for the clinical heterogeneity. The significance of these results is that they not only offer clues regarding the pathogenesis of Ph(+) disorders and highlight the potential clinical implications of a set of probes but also demonstrates what SAM can offer for the analysis of genome data.

Download Full-text

First Report of a de novo 10q23.31q23.33 Microdeletion: Obesity, Intellectual Disability and Microcephaly

Molecular Syndromology ◽

10.1159/000515400 ◽

2021 ◽

pp. 1-5

Author(s):

Ayberk Turkyilmaz ◽

Erdal Kurnaz ◽

Atilla Cayir

Keyword(s):

Intellectual Disability ◽

Array Cgh ◽

De Novo ◽

Chromosomal Abnormalities ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Autism Spectrum ◽

Comparative Genomic ◽

Facial Dysmorphism ◽

Genetic And Environmental Factors

Intellectual disability (ID) is characterized by limited or insufficient development of mental abilities, including intellectual functioning impairments, such as learning and understanding cause-effect relationships. Some cases have ID as the only finding and are called isolated cases. Conversely, cases accompanied by facial dysmorphism, microcephaly, autism spectrum disorder, epilepsy, obesity, and congenital anomalies are called syndromic developmental delay (DD)/ID. Isolated and syndromic DD/ID cases show extreme genetic heterogeneity. Genetic etiology can be detected in approximately 40% of the cases, whereas chromosomal abnormalities are observed in 25%. Obesity is a multifactorial disease in which both genetic and environmental factors play important roles. The role of heredity in obesity has been reported to be between 40 and 70%. Array-based comparative genomic hybridization (array-CGH) can detect CNVs in the whole genome at a higher resolution than conventional cytogenetic methods. Array-CGH is currently recommended as the first-tier genetic test for ID cases worldwide. In the present study, we aimed to evaluate clinical, radiological, and genetic analyses of a 12-year and 4-month-old girl with microcephaly, ID, and obesity. In the array-CGH analysis, a 3.1-Mb deletion, arr[GRGh37] 10q23.31g23.33 (92745793_95937944)×1 was detected, and this alteration was evaluated to be pathogenic. We consider that haploinsufficiency of the candidate genes (GPR120, KIF11, EXOC6, CYP26A1, CYP26C1, and LGI1) in the deletion region may explain microcephaly, ID, obesity, seizures, and ophthalmological findings in our patient. The investigation of 10q23.31q23.33 microdeletion in cases with syndromic obesity may contribute to molecular genetic diagnosis.

Download Full-text

3p14 De Novo Interstitial Microdeletion in a Patient with Intellectual Disability and Autistic Features with Language Impairment: A Comparison with Similar Cases

Case Reports in Genetics ◽

10.1155/2015/876348 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Ana Belén de la Hoz ◽

Hiart Maortua ◽

Ainhoa García-Rives ◽

María Jesús Martínez-González ◽

Maitane Ezquerra ◽

...

Keyword(s):

Language Impairment ◽

Array Comparative Genomic Hybridization ◽

De Novo ◽

Interstitial Deletion ◽

Comparative Genomic ◽

Facial Dysmorphism ◽

Chain Reaction ◽

Polymerase Chain ◽

Six Genes ◽

Genotype Correlation

To date, few cases of 3p proximal interstitial deletions have been reported and the phenotype and genotype correlation is not well understood. Here, we report a new case of a 3p proximal interstitial deletion. The patient is an 11-year-old female with speech and social interaction difficulties, learning disability, and slight facial dysmorphism, but no other major malformations. An 8 Mb de novo interstitial deletion at 3p14.2-p14.1, from position 60.461.316 to 68.515.453, was revealed by means of array comparative genomic hybridization and confirmed using quantitative reverse-transcription polymerase chain reaction assays. This region includes six genes:FEZF2, CADPS, SYNPR, ATXN7, PRICKLE, andMAGI1, that are known to have a role in neurodevelopment. These genes are located on the proximal side of the deletion. We compare our case with previously well-defined patients reported in the literature and databases.

Download Full-text

An Indian infant with de novo duplication of 16p chromosome: A rare genetic syndrome

Indian Journal of Medical Sciences ◽

10.25259/ijms_278_2020 ◽

2020 ◽

Vol 0 ◽

pp. 1-3

Author(s):

Manisha Goyal ◽

Ashok Gupta ◽

Mohammed Faruq ◽

Divya Shrivastava

Keyword(s):

Array Cgh ◽

De Novo ◽

Chromosomal Abnormalities ◽

Comparative Genomic ◽

Facial Dysmorphism ◽

Genetic Syndromes ◽

Genetic Syndrome ◽

Diagnostic Technology ◽

Chromosome 16P13.3 ◽

Indian Infant

Facial dysmorphism along with multiple congenital anomalies is observed in many genetic syndromes mostly in chromosomal microdeletion or duplication, which cannot be detected by conventional karyotype. Here, we report a case with facial dysmorphism, cleft palate, congenital heart defect, and umbilical hernia, diagnosed with duplication at chromosome 16p13.3 by array comparative genomic hybridization (CGH) at very early age. Array CGH is the advanced diagnostic technology; enable to diagnose chromosomal abnormalities earlier thus can provide appropriate medical management and prognostication.

Download Full-text

Jacobsen syndrome and neonatal bleeding: report on two unrelated patients

Italian Journal of Pediatrics ◽

10.1186/s13052-021-01108-2 ◽

2021 ◽

Vol 47 (1) ◽

Author(s):

Gregorio Serra ◽

Luigi Memo ◽

Vincenzo Antona ◽

Giovanni Corsello ◽

Valentina Favero ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Comparative Genomic ◽

Fish Analysis ◽

Variable Degree ◽

Jacobsen Syndrome ◽

Contiguous Gene ◽

Clinical Consequences ◽

11Q Deletion

Abstract Introduction In 1973, Petrea Jacobsen described the first patient showing dysmorphic features, developmental delay and congenital heart disease (atrial and ventricular septal defect) associated to a 11q deletion, inherited from the father. Since then, more than 200 patients have been reported, and the chromosomal critical region responsible for this contiguous gene disorder has been identified. Patients’ presentation We report on two unrelated newborns observed in Italy affected by Jacobsen syndrome (JBS, also known as 11q23 deletion). Both patients presented prenatal and postnatal bleeding, growth and developmental delay, craniofacial dysmorphisms, multiple congenital anomalies, and pancytopenia of variable degree. Array comparative genomic hybridization (aCGH) identified a terminal deletion at 11q24.1-q25 of 12.5 Mb and 11 Mb, in Patient 1 and 2, respectively. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletion for Patient 1; parents of Patient 2 refused further genetic investigations. Conclusions Present newborns show the full phenotype of JBS including thrombocytopenia, according to their wide 11q deletion size. Bleeding was particularly severe in one of them, leading to a cerebral hemorrhage. Our report highlights the relevance of early diagnosis, genetic counselling and careful management and follow-up of JBS patients, which may avoid severe clinical consequences and lower the mortality risk. It may provide further insights and a better characterization of JBS, suggesting new elements of the genotype-phenotype correlations.

Download Full-text

A de novo missense variant in MED13 in a patient with global developmental delay, marked facial dysmorphism, macroglossia, short stature, and macrocephaly

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.62238 ◽

2021 ◽

Author(s):

Alice P. Rogers ◽

Kathryn Friend ◽

Lesley Rawlings ◽

Christopher P. Barnett

Keyword(s):

Short Stature ◽

Developmental Delay ◽

De Novo ◽

Missense Variant ◽

Global Developmental Delay ◽

Facial Dysmorphism

Download Full-text

MED12-Related (Neuro)Developmental Disorders: A Question of Causality

Genes ◽

10.3390/genes12050663 ◽

2021 ◽

Vol 12 (5) ◽

pp. 663

Author(s):

Stijn van de Plassche ◽

Arjan PM de Brouwer

Keyword(s):

Developmental Disorders ◽

De Novo ◽

Expression Patterns ◽

Mediator Complex ◽

Gene Expression Patterns ◽

Facial Dysmorphism ◽

Regulation Of Transcription ◽

Feeding Difficulties ◽

Missense Variants ◽

Pathogenic Variants

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

Download Full-text