Copy number variations in a population with prune belly syndrome

Abstract

Prune Belly Syndrome (PBS) is a congenital multisystem myopathy with mild to lethal severity. While of uncertain etiology, 95% male predominance and familial occurrence suggest a genetic basis. As copy number variations (CNVs) can cause unexplained genetic disorders, we tested for novel CNVs in a large PBS population. We genotyped 21 unrelated PBS patients by high-resolution array comparative genomic hybridization (aCGH) and phenotyped using a novel PBS severity scoring system. Available parents were screened for detected CNV via quantitative PCR (qPCR). We additionally screened for recurrence of identified novel candidate CNVs on 106 PBS probands by qPCR. We identified 10 CNVs in 8 of 21 PBS patients tested (38%). Testing confirmed inheritance from an unaffected biological parent in 6 patients; parental samples were unavailable in 2 probands. One candidate CNV includes duplication of the X-chromosome AGTR2 gene, known to function in urinary tract development. Subsequent screening of the larger PBS cohort did not identify any recurrent CNVs. Presence of CNV did not correlate with PBS severity scoring. CNVs were uncommon in this large PBS population, but analysis of identified variants may inform disease pathogenesis and reveal targets for therapeutic intervention for this rare, severe disorder.

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

“…Lastly, there have been 12 published multiplex pedigrees without causal genes identified in most [19][20][21][23][24][25][26][27][28][29][30][31]. More recently, five autosomal genes, including CHRM3, HNF1β, ACTA2, ACTG2 and STIM1, have been reported with potentially causal DNA variants, including structural, copy number, and single nucleotide variants, however these genes each only account for one or two PBS cases or one PBS multiplex consanguineous kindred [32][33][34][35][36][37][38]. Moreover, none of the currently suggested candidate genes fit an X-linked recessive mode of inheritance and functional data is lacking for many of these candidate genetic variants.…”

PIEZO1 loss-of-function compound heterozygous mutations in the rare congenital human disorder Prune Belly Syndrome

“…At this point, most cases of PBS remain genetically undefined. In the last ten years, seven autosomal genes (MYOCD, CHRM3, HNF1β, ACTA2, ACTG2, STIM1 and MYH11) and one X-linked gene (FLNA) have been reported with potentially causal rare DNA variants, including structural variants, copy number variants, and single nucleotide variants 44 – 54 . Interestingly, FLNA, MYH11, ACTA2, and ACTG2 genes are involved in mechanosensation of the cell 55 – 58 .…”

Síndrome de Prune Belly en una paciente adolescente

“…En un estudio de Iqbal y colaboradores se identificaron dos pacientes con desequilibrio en el cromosoma X, y uno con duplicación del gen AGTR2 ubicado en dicho cromosoma, el cual está implicado en el desarrollo del tracto urinario. 8 En otro estudio se identificaron tres mutaciones del gen FLNA, implicado en la producción de la proteína filamina A, la cual regula la reticulación de actina que funciona en las células del músculo liso. 9 Además, se han propuesto teorías que implican alteraciones en diversas proteínas de contractilidad muscular visceral como resultado de mutaciones genéticas, incluyendo los genes ACTA2, ACTG2, MYH11, MYLK, MYOCD y HNF1B.…”

“…Algunas incluyen el origen genético heterogéneo, con la implicación de diversas proteínas de contractilidad muscular visceral o de alteraciones de los receptores muscarínicos colinérgicos M3, 6,7 o bien, que el modo de herencia está ligado al cromosoma X. 8,9 Otra propuesta describe que hay alteración en el desarrollo del mesodermo, lo cual explicaría las alteraciones morfológicas a nivel genitourinario, gastrointestinal y de otros sistemas. 10 El diagnóstico puede realizarse durante la gestación, a través de una ecografía obstétrica con evidencia de contornos irregulares en el abdomen asociado con un aumento de su circunferencia, anomalías del tracto urinario, oligohidramnios, ascitis fetal y uraco permeable.…”