Terminal 14q32.33 deletion as a novel cause of agammaglobulinemia

Geier, Christoph; Piller, Alexander; Eibl, Martha M.; Čižnár, Peter; Ilenčíková, Denisa; Wolf, Hermann M.

doi:10.1016/j.clim.2017.07.003

Cited by 4 publications

(4 citation statements)

References 18 publications

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“…A single SNP in chromosome 3q28 achieved genome-wide significance in the analysis of BCL (rs72439195; p = 3.69× 10 -8 ), and 90 regions yielded suggestive evidence, most of which have not been previously implicated in OFC formation. However, some of these regions, like 14q32.33 (lead SNP: rs61996057; p = 8.07× 10 -8 ; Figure S1A, Figure S2A, Figure S3, Table S2), have been implicated in syndromes with facial dysmorphisms (34)(35)(36). In the analysis of UCL, two loci reached genome-wide significance (8q24 and 1q32), both of which are recognized genetic risk loci for CL/P ( Figure S1B, Figure S2B, Table S3) (2, 4, 7-10).…”

Section: Resultsmentioning

confidence: 99%

“…For example, SNPs in 14q32.33 gave suggestive evidence of association for BCL, with a distinct effect only seen in BCL, and 2q13 yielded suggestive evidence of association for UCL. Microdeletions in both of these regions have been associated with syndromes that include facial dysmorphisms (34)(35)(36)(37). The 14q32.33 also contains JAG2 which is part of the Notch signaling pathway and is important for craniofacial development (55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

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The PAX1 locus at 20p11 is a modifier for bilateral cleft lip only

Curtis

Chang

Lee

et al. 2020

Preprint

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Nonsyndromic orofacial clefts (OFCs) are the most common craniofacial birth defect in humans and, like many complex traits, OFCs are phenotypically and etiologically heterogenous. The phenotypic heterogeneity of OFCs extends beyond the structures affected by the cleft (e.g., cleft lip (CL) and cleft lip and palate (CLP) to other features, such as the severity of the cleft. Here, we focus on bilateral and unilateral clefts as one dimension of OFC severity. Unilateral clefts are more frequent than bilateral clefts for both CL and CLP, but the genetic architecture of these subtypes is not well understood, and it is not known if genetic variants predispose for the formation of one subtype over another. Therefore, we tested for subtype-specific genetic associations in 44 bilateral CL (BCL) cases, 434 unilateral CL (UCL) cases, 530 bilateral CLP cases (BCLP), 1123 unilateral CLP (UCLP) cases, and unrelated controls (N = 1626), using the mixed-model approach implemented in GENESIS. While no novel loci were found in subtype-specific analyses comparing cases to controls, the genetic architecture of UCL was distinct compared to BCL, with 43.8% of suggestive loci (p < 1.0×10-5) having non-overlapping confidence intervals between the two subtypes. To further understand the genetic risk factors for severity differences, we then performed a genome-wide scan for modifiers using a similar mixed-model approach and found one genome-wide significant modifier locus on 20p11 (p = 7.53×10-9), 300kb downstream of PAX1, associated with higher odds of BCL compared to UCL, which also replicated in an independent cohort (p = 0.0018) and showed no effect in BCLP (p>0.05). We further found that SNPs at this locus were associated with normal human nasal shape. Taken together, these results suggest bilateral and unilateral clefts may have differences in their genetic architecture, especially between CL and CLP. Moreover, our results suggest BCL, the rarest form of OFC, may be genetically distinct from the other OFC subtypes. This expands our understanding of genetic modifiers for subtypes of OFCs and further elucidates the genetic mechanisms behind the phenotypic heterogeneity in OFCs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The PAX1 locus at 20p11 is a modifier for bilateral cleft lip only

Curtis

Chang

Lee

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Deletion of these genes may cause impaired immune system function (Youngs et al ., 2011). Geier et al (2017) reported a 20-year-old male with a terminal deletion of 14q32.33 and decreased serum immunoglobulin levels who had recurrent attacks of severe upper respiratory tract infection since the age of 2 years. Engels et al (2012) described five individuals with 14q32.32 terminal deletions.…”

Section: Discussionmentioning

confidence: 99%

A case of 14q terminal deletion syndrome and hemifacial microsomia with review of terminal 14q deletion cases

Keçeci',

Basdemirci,

Çaksen

2024

Clinical Dysmorphology

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“…Amplification of the CCNE1 locus in this region was synthetic lethal related, targeted by PKMYT1 kinase inhibition, and it was also a promising target in AFPGC, which warranted further research in HAS [ 10 , 33 ]. Deleted regions-associated studies were mainly involved in gastrointestinal defects, Peutz-Jeghers syndrome (19p13.3), and immunodeficiency (14q32.33) [ 34 , 35 , 36 , 37 ]. There were 32 regions specifically amplificated or deleted in HAS ( Figure S7C,D ), and the amplification of chr22q11.21 and deletions of chr1p36.21, chr7q11.21, chr7q22.1, chr9q12 as well as chr12q24.33 predicted a tendency of shorter OS.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Genomic Alterations in Hepatoid Adenocarcinoma of the Stomach and Identification of Clinically Actionable Alterations

Zhao

et al. 2022

Cancers

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Hepatoid adenocarcinoma of the stomach (HAS) is a rare malignancy with aggressive biological behavior. This study aimed to compare the genetic landscape of HAS with liver hepatocellular carcinoma (LIHC), gastric cancer (GC), and AFP-producing GC (AFPGC) and identify clinically actionable alterations. Thirty-eight cases of HAS were collected for whole-exome sequencing. Significantly mutated genes were identified. TP53 was the most frequently mutated gene (66%). Hypoxia, TNF-α/NFκB, mitotic spindle assembly, DNA repair, and p53 signaling pathways mutated frequently. Mutagenesis mechanisms in HAS were associated with spontaneous or enzymatic deamination of 5-methylcytosine to thymine and defective homologous recombination-related DNA damage repair. However, LIHC was characteristic of exposure to aflatoxin and aristolochic acid. The copy number variants (CNVs) in HAS was significantly different compared to LIHC, GC, and AFPGC. Aggressive behavior-related CNVs were identified, including local vascular invasion, advanced stages, and adverse prognosis. In 55.26% of HAS patients there existed at least one clinically actionable alteration, including ERBB2, FGFR1, CDK4, EGFR, MET, and MDM2 amplifications and BRCA1/2 mutations. MDM2 amplification with functional TP53 was detected in 5% of HAS patients, which was proved sensitive to MDM2 inhibitors. A total of 10.53% of HAS patients harbored TMB > 10 muts/Mb. These findings improve our understanding of the genomic features of HAS and provide potential therapeutic targets.

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Terminal 14q32.33 deletion as a novel cause of agammaglobulinemia

Cited by 4 publications

References 18 publications

The PAX1 locus at 20p11 is a modifier for bilateral cleft lip only

The PAX1 locus at 20p11 is a modifier for bilateral cleft lip only

A case of 14q terminal deletion syndrome and hemifacial microsomia with review of terminal 14q deletion cases

Comprehensive Analysis of Genomic Alterations in Hepatoid Adenocarcinoma of the Stomach and Identification of Clinically Actionable Alterations

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