Renal malformations in deletion 22q11.2 patients

Kujat, Annegret; Schulz, Marc Daniel; Strenge, Sibylle; Froster, Ursula G.

doi:10.1002/ajmg.a.31289

Cited by 20 publications

(14 citation statements)

References 10 publications

(9 reference statements)

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“…The observed renal and urogenital anomalies in central 22q11.2 deletion carriers are similar to and occurred with equal overall frequencies to those reported in carriers of the ∼3 Mb common deletion [Ryan et al, ; Stewart et al, ; Wu et al, ; Kujat et al, ]. The smallest deleted segment in subjects with an urogenital anomaly was the region between LCR22‐C and LCR22‐D.…”

Section: Discussionsupporting

confidence: 75%

Central 22q11.2 deletions

Rump

Leeuw

Essen

et al. 2014

American J of Med Genetics Pt A

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22q11.2 deletion syndrome is one of the most common microdeletion syndromes. Most patients have a deletion resulting from a recombination of low copy repeat blocks LCR22-A and LCR22-D. Loss of the TBX1 gene is considered the most important cause of the phenotype. A limited number of patients with smaller, overlapping deletions distal to the TBX1 locus have been described in the literature. In these patients, the CRKL gene is deleted. Haploinsufficiency of this gene has also been implicated in the pathogenesis of 22q11.2 deletion syndrome. To distinguish these deletions (comprising the LCR22-B to LCR22-D region) from the more distal 22q11.2 deletions (located beyond LCR22-D), we propose the term "central 22q11.2 deletions". In the present study we report on 27 new patients with such a deletion. Together with information on previously published cases, we review the clinical findings of 52 patients. The prevalence of congenital heart anomalies and the frequency of de novo deletions in patients with a central deletion are substantially lower than in patients with a common or distal 22q11.2 deletion. Renal and urinary tract malformations, developmental delays, cognitive impairments and behavioral problems seem to be equally frequent as in patients with a common deletion. None of the patients had a cleft palate. Patients with a deletion that also encompassed the MAPK1 gene, located just distal to LCR22-D, have a different and more severe phenotype, characterized by a higher prevalence of congenital heart anomalies, growth restriction and microcephaly. Our results further elucidate genotype-phenotype correlations in 22q11.2 deletion syndrome spectrum.

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Section: Discussionsupporting

confidence: 75%

Central 22q11.2 deletions

Rump

Leeuw

Essen

et al. 2014

American J of Med Genetics Pt A

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“…4,6,12,13 Although some of the hallmarks of this syndrome (e.g., heart defects) can be attributed in part to haploinsufficiency of TBX1 , 14–18 the identity of the genes that are responsible for such congenital kidney and urinary tract anomalies remains unknown.…”

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confidence: 99%

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

López-Rivera¹,

Liu

Verbitsky³

et al. 2017

N Engl J Med

126

121

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BACKGROUND The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. METHODS We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10−14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)

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“…The etiology of renal malformations in deletion 22q11 still remains unclear, but it is postulated that a single-gene defect within the DGCR is responsible for the development of the urogenital tract in early embryonic development (4). Described renal malformations in patients with 22q11 deletion syndrome are absent, dysplastic or multicystic kidneys, obstructive abnormalities, vesicoureteral reflux, nephron calcinosis, duplex kidney, and affect 10–36% of patients according to the different authors (7–9).…”

Section: Discussionmentioning

confidence: 99%

“…Also known as DiGeorge syndrome, velocardiofacial syndrome, and CATCH22 acronym (cardiac defects, abnormal faces, thymus hypoplasia, clef palate, and hypocalcemia) that outlines the main clinical features (2), this deletion presents an expansive phenotype with more than 180 clinical features described that involve every organ and system (3). It occurs in 1/4000 live births and constitutes the most frequent interstitial chromosomal aberration (4). …”

Section: Introductionmentioning

confidence: 99%

22q11 Deletion Syndrome and Urogenital Manifestations: A Clinicopathological Case Report

Vachette¹,

Grant²,

Joliniere³

et al. 2016

Front. Med.

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BackgroundDeletion in the chromosomal region 22q11 results from the abnormal development of the third and fourth pharyngeal pouches during embryonic life and presents an expansive phenotype with more than 180 clinical features described that involve every organ and system.History and signsA 23-year-old African woman presented for the first trimester echography, which revealed an isolated anechoic structure suggesting a ureteral dilatation. The suspicion of a malposition of great arteries in the second trimester indicated an amniocentesis leading to a diagnosis of 22q11 deletion.OutcomeAt 32 weeks, the patient was admitted for premature rupture of membranes and gave birth 2 weeks later to a male newborn who presented a respiratory distress syndrome and probably died secondary to a tracheal stenosis. Necropsy revealed typical clinical features of 22q11 deletion associated with left renal agenesis, hypospadias, and penile hypoplasia.ConclusionWe report a case of 22q11 deletion syndrome with typical clinical features associated with urogenital manifestations suspected at the first trimester ultrasound.

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Renal malformations in deletion 22q11.2 patients

Cited by 20 publications

References 10 publications

Central 22q11.2 deletions

Central 22q11.2 deletions

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

22q11 Deletion Syndrome and Urogenital Manifestations: A Clinicopathological Case Report

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