Molecular characterization of two patients with de novo interstitial deletions in 4q22–q24

Hilhorst‐Hofstee, Yvonne; Tümer, Zeynep; Born, Peter; Knijnenburg, Jeroen; Hansson, Kerstin; Yatawara, Vindhya; Steensberg, Jesper; Ullmann, Reinhard; Arkesteijn, Ger; Tommerup, Niels; Larsen, Lars Allan

doi:10.1002/ajmg.a.32977

Cited by 5 publications

(3 citation statements)

References 11 publications

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“…Interstitial deletions in the 4q21-q25 region have been reported in a small number of patients so far, and precise mapping of the breakpoints is described in only a few cases (17)(18)(19)(20)(21). Four of these patients had a deletion that considerably overlapped the one described in this study (molecular and clinical details summarized in Table 2).…”

Section: Discussionmentioning

confidence: 55%

Common Variable Immunodeficiency and Neurodevelopmental Delay Due to a 13Mb Deletion on Chromosome 4 Including the NFKB1 Gene: A Case Report

et al. 2022

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Syndromic immunodeficiencies are a heterogeneous group of inborn errors of immunity that can affect the development of non-immune organs and systems. The genetic basis of these immunodeficiencies is highly diverse, ranging from monogenic defects to large chromosomal aberrations. Antibody deficiency is the most prevalent immunological abnormality in patients with syndromic immunodeficiencies caused by chromosomal rearrangements, and usually manifests as a common variable immunodeficiency (CVID)-like phenotype. Here we describe a patient with a complex phenotype, including neurodevelopmental delay, dysmorphic features, malformations, and CVID (hypogammaglobulinemia, reduced pre-switch and switch memory B cells, and impaired vaccine response). Microarray-based comparative genomic hybridization (aCGH) revealed a 13-Mb deletion on chromosome 4q22.2-q24 involving 53 genes, some of which were related to the developmental manifestations in our patient. Although initially none of the affected genes could be linked to his CVID phenotype, subsequent reanalysis identified NFKB1 haploinsufficiency as the cause. This study underscores the value of periodic reanalysis of unsolved genetic studies performed with high-throughput technologies (eg, next-generation sequencing and aCGH). This is important because of the ongoing incorporation of new data establishing the relationship between genes and diseases. In the present case, NFKB1 had not been associated with human disease at the time aCGH was performed. Eight years later, reanalysis of the genes included in the chromosome 4 deletion enabled us to identify NFKB1 haploinsufficiency as the genetic cause of our patient’s CVID. In the future, other genes included in the deletion may be linked to human disease, allowing us to better define the molecular basis of our patient’s complex clinical phenotype.

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Section: Discussionmentioning

confidence: 55%

Common Variable Immunodeficiency and Neurodevelopmental Delay Due to a 13Mb Deletion on Chromosome 4 Including the NFKB1 Gene: A Case Report

et al. 2022

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“…The deletion in 4q22.2-q24 region in patient 166 is also a very rare CNVs, it was described in patients with intellectual disability, dysmorphic features and internal malformations (25,26).…”

Section: Discussionmentioning

confidence: 94%

Copy number variation analysis in 189 Romanian patients with global developmental delay/intellectual disability

Miclea

Osan

Bucerzan

et al. 2021

Preprint

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Developmental delay and intellectual disability represent a common pathology in general population, involving about 3% of the pediatric age population and more and more often the genetic etiology is proven. The aim of this study was to determine the clinically relevant copy number variants in patients diagnosed with global developmental delay/intellectual disability in our population, using the technology SNP array. Material and methods. We analyzed 189 patients diagnosed with GDD//ID, presented in Clinical Emergency Hospital for Children Cluj-Napoca. The patients were completely clinically investigated, including dysmorphic evaluation, internal malformation evaluation, psychiatric and neuropsychological examinations, metabolic evaluation, standard karyotyping. Genomic analysis was done using SNP array technique. Results. 50/189 patients (26.45%) presented pathogenic CNVs and uniparental disomy (32/189 patients, 16.93%) or VOUS (variants of unknown significance) (18/189 patients, 9.52%). Two patients presented uniparental disomy of chromosome 15, one with clinical phenotype of Prader-Willi syndrome and the other with clinical phenotype with Angelman syndrome. The recurrent pathogenic CNVs were seen in 18/32 patients (56%) with pathogenic findings (CNVs or uniparental disomy). Conclusions. These data encouraged to continue using a microarray genetic testing as useful test for the diagnostic performance together with other new tools as exome or genome sequencing for a global genome view in diseases which have not a specific phenotype, such as intellectual disability.

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“…Recently, array CGH has been used to characterize patients with 4q deletions in an attempt to elucidate genotype-phenotype correlations [Quadrelli et al, 2007b;Kaalund et al, 2008;Kitsiou-Tzeli et al, 2008;Sensi et al, 2008;Hillhorst-Hofstee et al, 2009;Rossi et al, 2009;Al-Owain et al, 2010;Bonnet et al, 2010;Chien et al, 2010;Moreira et al, 2010]. Previously published reports are limited to a small number of cases.…”

Section: Introductionmentioning

confidence: 99%

Genotype–phenotype analysis of 4q deletion syndrome: Proposal of a critical region

Strehle¹,

Liu

Rosenfeld³

et al. 2012

American J of Med Genetics Pt A

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Chromosome 4q deletion syndrome (4q- syndrome) is a rare condition, with an estimated incidence of 1 in 100,000. Although variable, the clinical spectrum commonly includes craniofacial, developmental, digital, skeletal, and cardiac involvement. Data on the genotype-phenotype correlation within the 4q arm are limited. We present detailed clinical and genetic information by array CGH on 20 patients with 4q deletions. We identified a patient who has a ∼465 kb deletion (186,770,069-187,234,800, hg18 coordinates) in 4q35.1 with all clinical features for 4q deletion syndrome except for developmental delay, suggesting that this is a critical region for this condition and a specific gene responsible for orofacial clefts and congenital heart defects resides in this region. Since the patients with terminal deletions all had cleft palate, our results provide further evidence that a gene associated with clefts is located on the terminal segment of 4q. By comparing and contrasting our patients' genetic information and clinical features, we found significant genotype-phenotype correlations at a single gene level linking specific phenotypes to individual genes. Based on these data, we constructed a hypothetical partial phenotype-genotype map for chromosome 4q which includes BMP3, SEC31A, MAPK10, SPARCL1, DMP1, IBSP, PKD2, GRID2, PITX2, NEUROG2, ANK2, FGF2, HAND2, and DUX4 genes.

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Molecular characterization of two patients with de novo interstitial deletions in 4q22–q24

Cited by 5 publications

References 11 publications

Common Variable Immunodeficiency and Neurodevelopmental Delay Due to a 13Mb Deletion on Chromosome 4 Including the NFKB1 Gene: A Case Report

Common Variable Immunodeficiency and Neurodevelopmental Delay Due to a 13Mb Deletion on Chromosome 4 Including the NFKB1 Gene: A Case Report

Copy number variation analysis in 189 Romanian patients with global developmental delay/intellectual disability

Genotype–phenotype analysis of 4q deletion syndrome: Proposal of a critical region

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