No abstract

The severe mental retardation and speech deficits associated with 22q13 terminal deletions have been attributed in large part to haploinsufficiency of SHANK3, which maps to all 22q13 terminal deletions, although more proximal genes are assumed to have minor effects. We report two children with interstitial deletions of 22q13 and two copies of SHANK3, but clinical features similar to the terminal 22q13 deletion syndrome, including mental retardation and severe speech delay. Both these interstitial deletions are completely contained within the largest terminal deletion, but do not overlap with the nine smallest terminal deletions. These interstitial deletions indicate that haploinsufficiency for 22q13 genes other than SHANK3 can have major effects on cognitive and language development. However, the relatively mild speech problems and normal cognitive abilities of a parent who transmitted her identical interstitial deletion to her more severely affected son suggests that the phenotype associated with this region may be more variable than terminal deletions and therefore contribute to the relative lack of correlation between clinical severity and size of terminal deletions. The phenotypic similarity between the interstitial deletions and non-overlapping small terminal 22q13 deletions emphasizes the general nonspecificity of the clinical picture of the 22q13 deletion syndrome and the importance of molecular analysis for diagnosis.

These data suggest that the gene for the proinflammatory chemokine interleukin-8 is involved in susceptibility to acute pyelonephritis during upper urinary tract infection in children with or without vesicoureteral reflux.

Congenital anomalies of the kidney and urinary tract, as well as primary vesico-ureteric reflux (VUR) and associated renal dysplasia, are the most relevant causes of end-stage renal failure in the pediatric population. In vivo and in vitro experimental studies have allowed the identification of several genes involved both in ureteric bud branching, ureteric elongation and insertion into the bladder, and in nephrogenesis. It has been proposed that both renal and ureteral abnormalities, as well as the associated renal hypo-dysplasia, may derive from a common mechanism as the result of a dysregulation of the normal developmental program. The large homologies between mice and the human genome suggest that the same genes could be involved both in rodent and human VUR. Furthermore, epidemiological observations suggest that not only syndromic but also isolated VUR is an inherited trait. Linkage analysis for homologous mouse genes in humans, genome-wide linkage studies in multigenerational families and association studies by polymorphisms support the hypothesis that VUR is genetically heterogeneous and is caused by a number of different genes acting with random environmental effects. The present teaching paper is an overview of the embryology and genetics of primary VUR and associated congenital reflux nephropathy.

Background and objectives: Medullary sponge kidney (MSK) is a rare nephropathy characterized by cystic anomalies of precalyceal ducts, nephrocalcinosis, renal stones, and tubule dysfunctions. Its association with various malformations and cases of familial aggregation supports the conviction that genetic factors are involved, but no genetic studies have been conducted to date. It is hypothesized that MSK is due to a disruption at the "ureteric bud/metanephric blastema" interface caused by critical developmental genes functioning abnormally.Design, setting, participants, & measurements: Fifty-five apparently sporadic MSK patients were analyzed by direct DNA sequencing of all exons and exon-intron boundaries of glial cell-derived neurotrophic factor (GDNF) gene and rearranged during transfection (RET) gene, which have a leading role in renal development.Results: Two novel variants were found in heterozygosity in the MSK case population: GDNF{ENST00000344622}: c.؊45G>C and c.؊27؉18G>A in a putative binding domain for paired-box 2 transcription factor. As a whole, eight patients showed these variations: four patients carried the c.[؊45G>C; ؊27؉18G>A] complex allele, and the others had the c.؊27؉18G>A alone. A case-control study revealed that these two alleles were significantly associated with MSK. Five of the eight cases were found to be familial, and the allele variants cosegregated with the disease in a seemingly dominant pattern of inheritance. Patients revealed no mutations in the RET gene.Conclusions: This is the first report identifying GDNF gene sequence variations in patients with MSK and suggesting a role for this gene in the pathogenesis of some cases of the disease.