CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

Cytochrome c oxidase (COX) catalyzes both electron transfer from cytochrome c to molecular oxygen and the concomitant vectorial proton pumping across the inner mitochondrial membrane. Studying a large family with multiple cases of neonatal ketoacidotic comas and isolated COX deficiency, we have mapped the disease locus to chromosome 17p13.1, in a region encompassing two candidate genes involved in COX assembly-namely, SCO1 and COX10. Mutation screening revealed compound heterozygosity for SCO1 gene mutations in the patients. The mutated allele, inherited from the father, harbored a 2-bp frameshift deletion (DeltaGA; nt 363-364) resulting in both a premature stop codon and a highly unstable mRNA. The maternally inherited mutation (C520T) changed a highly conserved proline into a leucine in the protein (P174L). This proline, adjacent to the CxxxC copper-binding domain of SCO1, is likely to play a crucial role in the tridimentional structure of the domain. Interestingly, the clinical presentation of SCO1-deficient patients markedly differs from that of patients harboring mutations in other COX assembly and/or maturation genes.

Hirschsprung disease (HSCR), the most common hereditary cause of intestinal obstruction, shows considerable variation and complex inheritance. Coding sequence mutations in RET, GDNF, EDNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). We conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 and 19q12 that seem to be necessary and sufficient to explain recurrence risk and population incidence. The gene at 10q11 is probably RET, supporting its crucial role in all forms of HSCR; however, coding sequence mutations are present in only 40% of linked families, suggesting the importance of noncoding variation. Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. This study demonstrates by a complete genetic dissection why the inheritance pattern of S-HSCR is nonmendelian.The molecular dissection of 'model' disorders is crucial to the elucidation of complex patterns of inheritance, which have been difficult to assess by other means 1-3 . HSCR is a neurocristopathy characterized by the absence of ganglion cells in the myenteric and submucosal plexuses of the gastrointestinal tract 4 . The phenotype usually occurs in isolation and is classified by extent of aganglionosis into long-segment (L-HSCR, 20% of affected individuals) and short-segment (S-HSCR, 80%) forms, each with distinct genetic characteristics 5 . HSCR is hereditary but nonmendelian with risk varying by gender, segment length and co-occurrence of non-enteric phenotypes 6 . We have previously concluded that RET is the major gene involved in HSCR, for several reasons: (i) only one affected family unlinked to RET has been reported 7 ; (ii) coding sequence mutations occur in 50% of familial and 15−35% of sporadic cases 8 ; (iii) even when the major mutation is in EDNRB, RET variants make some contribution to susceptibility 9 and (iv) homozygous Ret-null mice have full sex-independent penetrance of aganglinonosis 10 . Yet, RET mutations may not be sufficient to lead to aganglionosis, as the penetrance of mutant alleles is 65% in males and 45% in females 8 . RET is the major gene underlying HSCR primarily in families enriched for L-HSCR 5 . The genes critical for the complex inheritance of the much more common S-HSCR remain unknown.We carried out a genome search of the number and locations of genes conferring susceptibility to S-HSCR in 49 affected families ascertained through a proband with S-HSCR, using 371 tandem repeat polymorphisms at a map resolution of approximately 10 cM. With an incidence of 1 in 6,250 livebirths and a sibling recurrence risk of 3% (ref. 5), the risk ratio (λ) for S-HSCR is 187.5, which allowed us to identify the major segregating risk factors 6 . Consequently, we could both impute or refute the role of all known candidate genes (see Methods), independently assess the role of RET and identify new genes invol...