Resources for Genetics Professionals — Genes with Highly Homologous Gene Family Members or a Pseudogene(s)

Wallace SE, Bean LJH.

Publication Details

Estimated reading time: 7 minutes

Gene families are genes of similar sequence and function that arose through duplication of an ancestral gene.

A pseudogene is a sequence of DNA that has some homology with a coding gene. Although most pseudogenes have the same structural elements (promotors, splice sites, and introns) found in coding genes, they do not encode proteins as they are often disrupted by multiple pathogenic variants. Processed pseudogenes are mRNA sequences copied and inserted into the genome and do not contain promotors or introns. The human genome contains approximately 20,000 pseudogenes.

The presence of non-unique sequence within the genome interferes with molecular genetic testing for many genetic disorders. The genes listed in the table below are common examples of genes with non-unique sequence and their associated disorders. Target enrichment (by PCR amplification or pull-down methods) can simultaneously amplify or capture sequence from a gene and other homologous regions. In addition, presence of homologous next-generation sequence reads can lead to loss of data (reads mapping to more than one location are discarded), false negative, or false positive results. In some cases, the length and degree of homology do not interfere with sequence analysis.

Although specific assays have been developed to distinguish the sequence of medically important genes from homologous sequences, these complex techniques are not easily implemented across the entire exome. Therefore, laboratories performing exome sequencing often exclude the analysis of highly homologous exons to avoid errors.

Many additional homologous sequences that may or may not (depending on specific assay design) interfere with sequence analysis are known. Assay performance must be assessed by laboratories performing testing.

Table Icon


Genes with Highly Homologous Gene Family Members or a Pseudogene(s)


Literature Cited

  • Basgalupp SP, Siebert M, Vairo FP, Chami AM, Pinto LL, Carvalho GD, Schwartz IV. Use of a multiplex ligation-dependent probe amplification method for the detection of deletions/duplications in the GBA1 gene in Gaucher disease patients. Blood Cells Mol Dis. 2018;68:17-20. [PubMed: 27825739]

  • Bondeson ML, Dahl N, Malmgren H, Kleijer WJ, Tönnesen T, Carlberg BM, Pettersson U. Inversion of the IDS gene resulting from recombination with IDS-related sequences is a common cause of the Hunter syndrome. Hum Mol Genet. 1995;4:615–21. [PubMed: 7633410]

  • Hayward BE, De Vos M, Valleley EM, Charlton RS, Taylor GR, Sheridan E, Bonthron DT. Extensive gene conversion at the PMS2 DNA mismatch repair locus. Hum Mutat. 2007;28:424–30. [PubMed: 17253626]

  • Hong G, Park HD, Choi R, Jin DK, Kim JH, Ki CS, Lee SY, Song J, Kim JW. CYP21A2 mutation analysis in Korean patients with congenital adrenal hyperplasia using complementary methods: sequencing after long-range PCR and restriction fragment length polymorphism analysis with multiple ligation-dependent probe amplification assay. Ann Lab Med. 2015;35:535–9. [PMC free article: PMC4510508] [PubMed: 26206692]

  • Huizing M, Anikster Y, Gahl WA. Characterization of a partial pseudogene homologous to the Hermansky-Pudlak syndrome gene HPS-1; relevance for mutation detection. Hum Genet. 2000;106:370–3. [PubMed: 10798370]

  • Masson E, Le Maréchal C, Delcenserie R, Chen JM, Férec C. Hereditary pancreatitis caused by a double gain-of-function trypsinogen mutation. Hum Genet. 2008;123:521–9. [PubMed: 18461367]

  • Millson A, Lewis T, Pesaran T, Salvador D, Gillespie K, Gau CL, Pont-Kingdon G, Lyon E, Bayrak-Toydemir P. Processed pseudogene confounding deletion/duplication assays for SMAD4. J Mol Diagn. 2015;17:576–82. [PubMed: 26165824]

  • Pannicke U, Hönig M, Schulze I, Rohr J, Heinz GA, Braun S, Janz I, Rump EM, Seidel MG, Matthes-Martin S, Soerensen J, Greil J, Stachel DK, Belohradsky BH, Albert MH, Schulz A, Ehl S, Friedrich W, Schwarz K. The most frequent DCLRE1C (ARTEMIS) mutations are based on homologous recombination events. Hum Mutat. 2010;31:197–207. [PubMed: 19953608]

  • Pfendner EG, Uitto J, Gerard GF, Terry SF. Pseudoxanthoma elasticum: genetic diagnostic markers. Expert Opin Med Diagn. 2008;2:63–79. [PubMed: 23485117]

  • Rozmahel R, Heng HH, Duncan AM, Shi XM, Rommens JM, Tsui LC. Amplification of CFTR exon 9 sequences to multiple locations in the human genome. Genomics. 1997;45:554–61. [PubMed: 9367680]

  • Takayanagi M, Kure S, Sakata Y, Kurihara Y, Ohya Y, Kajita M, Tada K, Matsubara Y, Narisawa K. Human glycine decarboxylase gene (GLDC) and its highly conserved processed pseudogene (psiGLDC): their structure and expression, and the identification of a large deletion in a family with nonketotic hyperglycinemia. Hum Genet. 2000;106:298–305. [PubMed: 10798358]

  • Vanita A, Singh JR, Sarhadi VK, Singh D, Reis A, Rueschendorf F, Becker-Follmann J, Jung M, Sperling K. A novel form of "central pouchlike" cataract, with sutural opacities, maps to chromosome 15q21-22. Am J Hum Genet. 2001;68:509–14. [PMC free article: PMC1235284] [PubMed: 11133359]

  • Vaughn CP, Hart KJ, Samowitz WS, Swensen JJ. Avoidance of pseudogene interference in the detection of 3' deletions in PMS2. Hum Mutat. 2011;32:1063–71. [PubMed: 21618646]

  • Vona B, Hofrichter MA, Neuner C, Schröder J, Gehrig A, Hennermann JB, Kraus F, Shehata-Dieler W, Klopocki E, Nanda I, Haaf T. DFNB16 is a frequent cause of congenital hearing impairment: implementation of STRC mutation analysis in routine diagnostics. Clin Genet. 2015;87:49–55. [PMC free article: PMC4302246] [PubMed: 26011646]

Suggested Reading

  • Brodehl A, Ferrier RA, Hamilton SJ, Greenway SC, Brundler MA, Yu W, Gibson WT, McKinnon ML, McGillivray B, Alvarez N, Giuffre M, Schwartzentruber J., FORGE Canada Consortium. Gerull B. Mutations in FLNC are associated with familial restrictive cardiomyopathy. Hum Mutat. 2016;37:269–79. [PubMed: 26666891]

  • Valdés-Mas R, Gutiérrez-Fernández A, Gómez J, Coto E, Astudillo A, Puente DA, Reguero JR, Álvarez V, Morís C, León D, Martín M, Puente XS, López-Otín C. Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy. Nat Commun. 2014;5:5326. [PubMed: 25351925]