Large deletion causing the TSC2-PKD1 contiguous gene syndrome without infantile polycystic disease

Tuberous sclerosis complex (TSC) is a genetic disorder characterised by hamartomatous growth abnormalities in many organs. Epilepsy and mental retardation, typical skin manifestations, intracerebral hamartoma, renal angiomyolipoma, and pulmonary lymphangioleiomyomatosis are among the major diagnostic features of TSC.1 TSC is thought to affect approximately 1 in every 6000 newborns. It has an autosomal dominant inheritance pattern, but an estimated 60% of all cases involve new mutations. TSC exhibits locus heterogeneity with two identified genes, one on 9q34 ( TSC1 ) and the other on 16p13 ( TSC2 ).2 The TSC2 gene lies immediately adjacent to PKD1 , the major gene causing autosomal dominant polycystic kidney disease (ADPKD). Both genes are in a tail to tail orientation only 60 bp apart. In 1994, a “contiguous gene syndrome” was described, involving large deletions disrupting both the TSC2 gene and the PKD1 gene.3 Although, overall, 25% to 32% of patients with TSC show some degree of renal cyst formation,4,5 the six cases described in the first report all presented during early childhood with markedly enlarged polycystic kidneys.3 Later reports of the PKD1 - TSC2 contiguous gene syndrome further supported the notion that this disorder is typically associated with severe juvenile polycystic kidney disease.6–8 A systematic mutational analysis of 27 unrelated patients with TSC and multiple bilateral renal cysts showed that 22 had contiguous deletions of TSC2 and PKD1. In 17 patients with constitutional deletions, the median age of presentation was six months (range 1 month to 10 years), with 83% of patients presenting with abdominal masses or distension owing to large cysts. Renal cystic disease was comparatively mild in the patients without the contiguous gene syndrome.7 Here, we present a case of a patient with an exceptionally large, de novo, germline deletion involving the entire TSC2 and …