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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

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

, MD and , PhD.

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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.

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

Gene 1Homologous Genes and PseudogenesDisorder Caused by Pathogenic Variants in this Gene 2Proportion of Affected Individuals with Pathogenic Variants in This Gene
ABCC6 3 ABCC6P1
ABCC6P2 		Pseudoxanthoma elasticum 100%
ABCD1 ≥5 pseudogenes X-linked adrenoleukodystrophy 100%
ACTB ≥18 pseudogenes Baraitser-Winter syndrome cerebrofrontofacial syndrome >60%
AK2 AK2P1
AK2P2 		Reticular dysgenesis (See X-Linked Severe Combined Immunodeficiency.)100%
ALG1 ≥8 pseudogenesALG1-CDG (CDG-type Ik) (See Congenital Disorders of N-linked Glycosylation & Multiple Pathway Overview.)100%
ANKRD11 LOC100419906
LOC100287912 		KBG syndrome 100%
ASL ASLP1 Argininosuccinate lyase deficiency 100%
ASS1 ≥14 pseudogenes Citrullinemia type I 100%
BANF1 ≥5 pseudogenesNestor-Guillermo progeria syndrome (OMIM 614008)100%
BMPR1A BMPR1APS1
BMPR1APS2 		Juvenile polyposis syndrome 20%-25%
C4A CYP21A C4A deficiency (OMIM 614380)100%
C4B CYP21A C4B deficiency (OMIM 614379)100%
CA5A CA5AP1 Carbonic anhydrase VA deficiency 100%
CDC42 ≥9 pseudogenesTakenouchi-Kosaki syndrome (OMIM 616737)2 individuals
CEL CELP Diabetes-pancreatic exocrine dysfunction syndrome (OMIM 609812)2 families
CFH CFHR1
CFHR2
CFHR3
CFHR4 		Genetic atypical hemolytic-uremic syndrome ~50%
CFH CFHR5 C3 glomerulopathy ~10%
CFTR 4 CFTRP1
CFTRP3 		Cystic fibrosis & congenital absence of the vas deferens 100%
CHEK2 ≥5 pseudogenesBreast cancer susceptibility (OMIM 114480)<5%
Prostate cancer susceptibility (OMIM 176807)
CORO1A LOC606724 Immunodeficiency 8 (OMIM 615401)100%
CRIPTO (TDGF1)≥7 pseudogenes Holoprosencephaly 2 individuals
CRYBB2 5 CRYBB2P1 Cataract 3, multiple types (OMIM 601547)100%
CYCS ≥37 pseudogenesThrombocytopenia, AD, nonsyndromic, type IV (OMIM 612004)100%
CYP21A2 6 CYP21A1P 21-hydroxylase-deficient congenital adrenal hyperplasia 100%
DCLRE1C 7 DCLRE1CP1 Omenn syndrome (OMIM 603554)>70 individuals
SCID Athabaskan (OMIM 602450)100%
DDX11 ≥6 pseudogenes Warsaw breakage syndrome 100%
DHFR ≥4 pseudogenesMegaloblastic anemia due to dihydrofolate reductase deficiency (OMIM 613839)100%
DIS3L2 DIS3L2P1 Perlman syndrome (OMIM 267000)100%
DPY19L2 ≥5 pseudogenesGlobozoospermia, spermatogenic failure (OMIM 613958)100%
EIF4E ≥5 pseudogenesAutism (OMIM 615091)3 families
FANCD2 FANCD2P1 Fanconi anemia ~3%
FLNC LOC392787 Hypertrophic cardiomyopathy (OMIM 102565)8 families
Restrictive cardiomyopathy (OMIM 617047)2 families
Distal ABD-filaminopathy100%
Myofibrillar myopathy (OMIM 609524)3%
GBA1 (GBA) 8GBA1LP (GBAP) Gaucher disease 100%
GCSH ≥8 pseudogenes Nonketotic hyperglycinemia <1%
GJA1 GJA6P
GJA1P1 		Oculodentodigital dysplasia (OMIM 164200)100%
Craniometaphyseal dysplasia, AR (OMIM 218400)100%
Palmoplantar keratoderma and congenital alopecia type 1 (OMIM 104100)100%
Hypoplastic left heart syndrome (OMIM 241550)8 individuals
GK GK3P
GK6P
GK4P 		Glycerol kinase deficiency (OMIM 307030)100%
GLDC 9 GLDCP1 Nonketotic hyperglycinemia 70%-75%
GLUD1 ≥6 pseudogenes Familial hyperinsulinism 5%
GNAQ GNAQP1 Sturge-Weber syndrome (OMIM 185300)88%
HBA1 10
HBA2		 HBAP1
HBZP 		Alpha-thalassemia 100%
HBB HBBP1 Sickle cell disease 100%
Beta-thalassemia
HCN4 ≥2 pseudogenes Brugada syndrome <1%
HPS1 11 LOC100500719 Hermansky-Pudlak syndrome 75% of Puerto Ricans;
44% of individuals not of Puerto Rican descent
HSPD1 ≥23 pseudogenesHypomyelinating leukodystrophy (OMIM 612233)2 individuals
Hereditary spastic paraplegia (OMIM 605280)1 family
HYDIN HYDIN2 Primary ciliary dyskinesia Founder variant in Faroe Islands; 1 additional family
IDS 12 IDSP1 Mucopolysaccharidosis type II 100%
IFT122 LOC653712 Cranioectodermal dysplasia ~10%
IKBKG IKBKGP1 Incontinentia pigmenti ~75%
KAL1 KALP Kallmann syndrome (See Isolated Gonadotropin-Releasing Hormone Deficiency.)5%-10%
KRT16 ≥5 pseudogenes Pachyonychia congenita 29%
Palmoplantar keratoderma, nonepidermolytic (focal) (OMIM 613000)≥5 families
KRT6A ≥4 pseudogenes Pachyonychia congenita 42%
KRT86 KRT87P
KRT88P 		Monilethrix (OMIM 158000)≥4 families
LEFTY2 LEFTY3 Left-right axis malformations (OMIM 601877)2 individuals
MATR3 LOC100499497
LOC100499496
LOC401957 		Amyotrophic lateral sclerosis type 21 (OMIM 606070)5 families
NCF1 NCF1B
NCF1C 		Chronic granulomatous disease 20%
NF1 ≥11 pseudogenes Neurofibromatosis type 1 100%
NLRP7 LOC100421039 Recurrent hydatidiform mole (OMIM 231090)~75%
NOTCH2 NOTCH2P1 Alagille syndrome 1%-2%
Hajdu-Cheney syndrome (OMIM 102500)100%
OCLN LOC647859Band-like calcification with simplified gyration and polymicrogyria (OMIM 251290)100%
OPHN1 ARHGAP42P3 X-linked intellectual disability with cerebellar hypoplasia and distinctive facial appearance (OMIM 300486)8 families
OTOA LOC653786 Deafness, AR, type 22 (OMIM 607038)100%
PHKA1 PHKA1P1 Phosphorylase kinase deficiency ~17%
PIK3CA LOC100422375 PIK3CA-related segmental overgrowth 100%
PKD1 ≥7 pseudogenes Polycystic kidney disease, AD 85%
PLEKHM1 PLEKHM1P1 Osteopetrosis, AR type 6 (OMIM 611497)100%
PMM2 PMM2P1 PMM2-CDG (CDG-Ia) 100%
PMS2 13≥14 pseudogenes Lynch syndrome <5%
PRODH LOC440792 Hyperprolinemia, type 1 (OMIM 239500)100%
PROS1 PROS2P Thrombophilia due to protein S deficiency (OMIM 176880)100%
PRSS1 14 PRSS3P2
PRSS3P1 		Hereditary pancreatitis (See Pancreatitis Overview.)60%-100%
PTEN PTENP1 PTEN hamartoma tumor syndrome 100%
RBM8A RBM8B Thrombocytopenia absent radius syndrome 100%
RPS17 ≥16 pseudogenes Diamond-Blackfan anemia ~1%
RPS19 ≥7 pseudogenes Diamond-Blackfan anemia 25%
SALL1 SALL1P1 Townes-Brocks syndrome 75%
SBDS 15 SBDSP Shwachman-Diamond syndrome 100%
SDHA ≥4 pseudogenes Hereditary paraganglioma-pheochromocytoma syndromes 1%-3%
SDHC ≥5 pseudogenes Hereditary paraganglioma-pheochromocytoma syndromes 4%-8%
SDHD ≥7 pseudogenes Hereditary paraganglioma-pheochromocytoma syndromes ~30%
SFTPA2 SFTPA3P Idiopathic pulmonary fibrosis (See Familial Pulmonary Fibrosis.)2 families
SLC25A15 ≥5 pseudogenes Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome 100%
SLC6A8 SCL6A10P
SCL6A10PB 		Creatine deficiency syndromes 56%
SMAD4 16≥1 pseudogene (not named)Juvenile polyposis syndrome
± Hereditary hemorrhagic telangiectasia		20%
SMN1
SMN2 		SMNP
LOC100132090 		Spinal muscular atrophy 100%
STRC 17 STRCP1 STRC-related autosomal recessive hearing loss 6%-11%
TARDBP LOC643387
TARDBPP1
TARDBPP2 		TARDBP-related amyotrophic lateral sclerosis-frontotemporal dementia 100%
TBX20 LOC100418730 ASD type 4 (OMIM 611363)3 families
TIMM8A TIMM8AP1 Deafness-dystonia-optic neuronopathy syndrome 13 individuals
TMEM231 LOC100420067 Joubert syndrome 2 families & 2 individuals
TNXB TNXA TNXB-related classic-like Ehlers-Danlos syndrome 100%
TPI1 ≥4 pseudogenesHemolytic anemia due to triosephosphate isomerase deficiency (OMIM 615512)100%
TUBA1A TUBA3GP
LOC100129818 		Lissencephaly and other complex cortical malformations (See Tubulinopathies Overview.)37% of classic lissencephaly
TUBB2B TUBB8P4
TUBB4BP2
TUBB2BP1 		Polymicrogyria-like cortical dysplasia (See Tubulinopathies Overview.)87.5%
TYR TYRL Oculocutaneous albinism type I (OMIM 203100, 606952)100%
UBE3A UBE3AP2
UBE3AP1 		Angelman syndrome ~11%
VWF VWFP1 von Willebrand disease 100%

AD = autosomal dominant; AR = autosomal recessive; ASD = atrial septal defect

1.

Included in this table are genes that have: (1) one or more identified pseudogenes; and (2) pathogenic variants identified in more than one individual or family. Genes from the same gene family are listed together.

2.

For more information see hyperlinked GeneReview. An OMIM phenotype entry is provided if a GeneReview is not available.

3.

Two pseudogenes are almost identical to ABCC6 [Pfendner et al 2008].

4.

Duplication of exon 10 [Rozmahel et al 1997]

5.

Gene conversion between CRYBB2 and CRYBB2P1 was reported by Vanita et al [2001].

6.

Testing the proband and parents may be required to clarify results [Hong et al 2015].

7.

The most common DCLRE1C pathogenic variant is a deletion resulting from homologous recombination of DCLRE1C and the pseudogene [Pannicke et al 2010].

8.

GBA1LP is 96% homologous to GBA1 [Basgalupp et al 2018].

9.

The processed pseudogene has 97.5% homology to the coding sequence of GLDC [Takayanagi et al 2000].

10.

HBA1 and HBA2 have identical coding regions. This gene family also includes the embryonically expressed HBZ, HBD, and HBQ1.

11.

The pseudogene has 95% homology to HPS1; exon 6 is identical [Huizing et al 2000].

12.

9% of pathogenic variants are complex rearrangements with the pseudogene. The pseudogene is 96% homologous to IDS [Bondeson et al 1995].

13.

Ongoing evolutionary sequence exchange between PMS2 and one pseudogene (PMS2CL) has led to unreliable reference sequences and false positive and false negative results on sequencing [Hayward et al 2007] (see also Vaughn et al [2011]).

14.

Regardless of the sequencing method employed, primers must be carefully chosen and validated to amplify the fragment for the correct gene and transcript. Thus, a multistep method is required to verify the presence of a pathogenic variant in PRSS1 [Masson et al 2008].

15.

Interpretations may be difficult as the extent of variation in SBDSP is not known. SBDSP is 97% homologous to SBDS.

16.

The presence of a processed pseudogene led to false positive MLPA results in some individuals [Millson et al 2015].

17.

STRCP1 is 99.6% homologous to STRC [Vona et al 2015].

References

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]
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