Compound heterozygous and mosaic mutations in kidney cancer predisposition syndromes

While autosomal dominant mutation of causative genes are known to cause the kidney cancer predisposition syndromes HLRCC, TSC, VHL and BHD, a number of studies suggest that compound heterozygous and mosaic mutations of these genes may also contribute to disease.

Biallelic mutations in the HLRCC gene FH, whether due to homozygosity or compound heterozygosity, cause fumarase deficiency – a severe neurological syndrome that affects children in early infancy. A few FH mutations have been reported in cases of both HLRCC and fumarase deficiency (Bayley et al., 2008), suggesting that the parents of children with fumarase deficiency must have HLRCC. However, the parents of two siblings with fumarase deficiency each carried one inactivating FH mutation but were both negative for any of the symptoms of HLRCC (Mroch et al., 2012), suggesting that the pattern of disease may depend on the precise mutations present in the family.

Two missense founder VHL mutations in the Chuvash and Croatian populations are known to cause polycythaemia, characterised by the overproliferation of red blood cells (Tomasic et al., 2013). Additionally, two American polycythaemic siblings were found to carry compound heterozygous missense mutations in VHL (Lorenzo et al., 2013). However, none of these patients or their parents are reported to have any of the symptoms of VHL, indicating that – as is the case in HLRCC and FH – there is possibly some genotype-phenotype correlation between VHL mutations and symptoms.

Recently, next generation sequencing (NGS), which is far more sensitive than traditional methods, was used to sequence blood from a cohort of 8 patients who had the clinical symptoms of VHL, but no VHL mutation had been found using conventional diagnostic methods (Coppin et al., 2013). Two patients were found to carry mosaic VHL mutations at an allele frequency of 5.7% and 1.7% respectively. Interestingly, these two patients had the most severe and classic symptoms of VHL, suggesting that mosaic mutations do not only cause mild and late onset forms of disease, as has been observed in TSC (Kwiatkowski et al., 2010). Indeed, it is likely that the severity of symptoms caused by mosaic mutations will depend on the gene, the precise mutation, the tissues affected and interactions with genetic modifiers.

No compound heterozygous FLCN mutations have been reported, which could be due to the fact that biallelic loss of FLCN is embryonic lethal in mouse models of BHD (Hasumi et al., 2009). However, compound heterozygosity with the PTEN tumour suppressor gene was found to be the likely cause of oncocytic tumours specifically in the context of BHD and Cowden Syndrome (Pradella et al., 2013), showing how interactions between genes can contribute to disease.

There are no reported cases of BHD patients carrying mosaic FLCN mutations. However, roughly 10% of patients with the clinical symptoms of BHD are not found to have a BHD mutation (Toro et al., 2008). As in the VHL cohort, it is possible that mosaic mutations account for some of these cases. Mosaicism may also account for some of the varied severity and symptoms seen between BHD cases.

While it has been technically difficult to find pathogenic mosaic and compound heterozygous mutations involving multiple genes, the advent of NGS technology allows researchers to find both types of mutation without any prior knowledge of the genetic basis of the disease they are investigating. Large scale projects like the 100k genomes project will be able to determine what proportion of human disease is due to mosaicism or compound heterozygosity, thus further elucidating how genetics affects health and disease.


  • Bayley JP, Launonen V, & Tomlinson IP (2008). The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. BMC medical genetics, 9 PMID: 18366737
  • Coppin L, Grutzmacher C, Crépin M, Destailleur E, Giraud S, Cardot-Bauters C, Porchet N, & Pigny P (2013). VHL mosaicism can be detected by clinical next-generation sequencing and is not restricted to patients with a mild phenotype. European journal of human genetics : EJHG PMID: 24301059
  • Hasumi Y, Baba M, Ajima R, Hasumi H, Valera VA, Klein ME, Haines DC, Merino MJ, Hong SB, Yamaguchi TP, Schmidt LS, & Linehan WM (2009). Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proceedings of the National Academy of Sciences of the United States of America, 106 (44), 18722-7 PMID: 19850877
  • Kwiatkowski DJ (2010). Genetics of Tuberous Sclerosis Complex. Tuberous Sclerosis Complex: Genes, Clinical Features and Therapeutics DOI: 10.1002/9783527630073.ch4
  • Lorenzo FR, Yang C, Lanikova L, Butros L, Zhuang Z, & Prchal JT (2013). Novel compound VHL heterozygosity (VHL T124A/L188V) associated with congenital polycythaemia. British journal of haematology, 162 (6), 851-3 PMID: 23772956
  • Mroch AR, Laudenschlager M, & Flanagan JD (2012). Detection of a novel FH whole gene deletion in the propositus leading to subsequent prenatal diagnosis in a sibship with fumarase deficiency. American journal of medical genetics. Part A, 158A (1), 155-8 PMID: 22069215
  • Pradella LM, Lang M, Kurelac I, Mariani E, Guerra F, Zuntini R, Tallini G, MacKay A, Reis-Filho JS, Seri M, Turchetti D, & Gasparre G (2013). Where Birt-Hogg-Dubé meets Cowden syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours. European journal of human genetics : EJHG, 21 (10), 1169-72 PMID: 23386036
  • Tomasic NL, Piterkova L, Huff C, Bilic E, Yoon D, Miasnikova GY, Sergueeva AI, Niu X, Nekhai S, Gordeuk V, & Prchal JT (2013). The phenotype of polycythemia due to Croatian homozygous VHL (571CG:H191D) mutation is different from that of Chuvash polycythemia (VHL 598CT:R200W). Haematologica, 98 (4), 560-7 PMID: 23403324
  • Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, & Linehan WM (2008). BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. Journal of medical genetics, 45 (6), 321-31 PMID: 18234728

Leave a Reply