Novel interstitial deletion of 10q24.3–25.1 associated with multiple congenital anomalies including lobar holoprosencephaly, cleft lip and palate, and hypoplastic kidneys

Peltekova, Iskra; Hurteau-Millar, Julie; Armour, Christine M.

doi:10.1002/ajmg.a.36740

Cited by 14 publications

(8 citation statements)

References 22 publications

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“…Interestingly, a female patient with a novel heterozygous interstitial 5.54 Mb deletion at 10q24.31-q25.1 was previously reported [13]. This defect involved 90+ genes, including NFKB2, and the patient presented at birth with lobar holoprosencephaly, cleft lip and palate, and hypoplastic kidneys, among multiple congenital anomalies.…”

Section: Discussionmentioning

confidence: 99%

A Nonsense N –Terminus NFKB2 Mutation Leading to Haploinsufficiency in a Patient with a Predominantly Antibody Deficiency

et al. 2020

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The noncanonical NF-κB pathway is implicated in diverse biological and immunological processes. Monoallelic C-terminus loss-of-function and gain-of-function mutations of NFKB2 have been recently identified as a cause of immunodeficiency manifesting with common variable immunodeficiency (CVID) or combined immunodeficiency (CID) phenotypes. Herein we report a family carrying a heterozygous nonsense mutation in NFKB2 (c.809G > A, p.W270*). This variant is associated with increased mRNA decay and no mutant NFKB2 protein expression, leading to NFKB2 haploinsufficiency. Our findings demonstrate that bona fide NFKB2 haploinsufficiency, likely caused by mutant mRNA decay and protein instability leading to the transcription and expression of only the wild-type allele, is associated with clinical immunodeficiency, although with incomplete clinical penetrance. Abnormal B cell development, hypogammaglobulinemia, poor antibody response, and abnormal noncanonical (but normal canonical) NF-κB pathway signaling are the immunologic hallmarks of this disease. This adds a third allelic variant to the pathophysiology of NFKB2-mediated immunodeficiency disorders.

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Section: Discussionmentioning

confidence: 99%

A Nonsense N –Terminus NFKB2 Mutation Leading to Haploinsufficiency in a Patient with a Predominantly Antibody Deficiency

et al. 2020

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“…Immunoglobulin levels were also demonstrated normal. NFKB2 is also deleted in the patients described by Peltekova et al, 2014, andTaylor et al, 2002, but recurrent infections were not described in those reports.…”

Section: Discussionmentioning

confidence: 94%

Clinical delineation of an adult female patient with a rare interstitial 10q24.32q25.1 microdeletion

Jehee

Bouma²,

Bouman

2021

Clinical Dysmorphology

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Interstitial deletions encompassing the 10q24.32q25.1 region are rare. Only three patients have been reported in literature to date. We describe a 44-year-old female with a 2.8 Mb microdeletion in 10q24.32q25.1. Clinical findings in this patient are delineated and compared to previously reported patients with (partly) overlapping microdeletions. Based on the few descriptions available in the literature, the major phenotypic features of microdeletion 10q24.32q25.1 seem to be profound developmental delay, severe intellectual disability, short stature, cleft lip and palate, multiple congenital malformations (brain, kidney and cardiac), ophthalmic problems and an increased risk to develop basal cell carcinoma. As far as we are aware, this is the first report of an adult patient with a 10q24.32q25.1 microdeletion in literature. Suggestions are made regarding the medical work-up for newly identified patients with a 10q24.32q25.1 microdeletion as well as for a possible interaction of the compound deletion of SUFU and FGF8 in midline craniofacial abnormalities.

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“…The associated variants phenotype is PAPRS in 52.8% of reports, 18% are CAKUT with or without ocular findings, 16% are RHD, 6.6% are FSGS, and 6.6% are ocular abnormalities ranging from myopia to nerve optic dysplasia without renal phenotype. The database also reports six chromosomic alterations: a balanced translocation (10:13) with a breakpoint on the PAX2 locus in intron 3 or 4 (10q24.3q12.3), two large deletions encompassing 90 genes including PAX2 , and other three deletions encompassing 2 to 44 genes including PAX2 [ 11 , 16 , 17 , 18 , 19 , 20 ]. Although a complete deletion of the gene has been described in patients with renal phenotype only, PAX2 mutations have never been reported in subjects with ocular phenotype only.…”

Section: Discussionmentioning

confidence: 99%

PAX2 and CAKUT Phenotypes: Report on Two New Variants and a Review of Mutations from the Leiden Open Variation Database

Negrisolo

Benetti

2023

IJMS

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PAX2 is a transcription factor expressed during embryogenesis in the eye, ear, CNS, and genitourinary tract, and is one of the major regulators of kidney development. Mutations in this gene are associated with papillorenal syndrome (PAPRS), a genetic condition characterized by optic nerve dysplasia and renal hypo/dysplasia. In the last 28 years, many cohort studies and case reports highlighted PAX2’s involvement in a large spectrum of kidney malformations and diseases, with or without eye abnormalities, defining the phenotypes associated with PAX2 variants as “PAX2-related disorders”. Here, we reported two new sequence variations and reviewed PAX2 mutations annotated on the Leiden Open Variation Database 3.0. DNA was extracted from the peripheral blood of 53 pediatric patients with congenital abnormalities of the kidney and urinary tract (CAKUT). PAX2 gene-coding exonic and flanking intronic regions were sequenced with Sanger technology. Two unrelated patients and two twins carrying one known and two unknown PAX2 variations were observed. The frequency of PAX2-related disorders in this cohort was 5.8%, considering all CAKUT phenotypes (16.7% in the PAPRS phenotype and 2.5% in non-syndromic CAKUT). Although PAX2 mutations have a higher frequency in patients with PAPRS or non-syndromic renal hypoplasia, from the review of variants reported to date in LOVD3, PAX2-related disorders are detected in pediatric patients with other CAKUT phenotypes. In our study, only one patient had a CAKUT without an ocular phenotype, but his twin had both renal and ocular involvement, confirming the extreme inter- and intrafamilial phenotypic variability.

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Novel interstitial deletion of 10q24.3–25.1 associated with multiple congenital anomalies including lobar holoprosencephaly, cleft lip and palate, and hypoplastic kidneys

Cited by 14 publications

References 22 publications

A Nonsense N –Terminus NFKB2 Mutation Leading to Haploinsufficiency in a Patient with a Predominantly Antibody Deficiency

A Nonsense N –Terminus NFKB2 Mutation Leading to Haploinsufficiency in a Patient with a Predominantly Antibody Deficiency

Clinical delineation of an adult female patient with a rare interstitial 10q24.32q25.1 microdeletion

PAX2 and CAKUT Phenotypes: Report on Two New Variants and a Review of Mutations from the Leiden Open Variation Database

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