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

Stephanie E Wallace; Lora JH Bean

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

Wallace SE, Bean LJH.

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.

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

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]

Publication Details

Author Information and Affiliations

Stephanie E Wallace, MD

Senior Editor, GeneReviews

Clinical Professor, Pediatrics
University of Washington
Seattle, Washington

Email: ude.wu@2rotide

Lora JH Bean, PhD

Molecular Genetics Editor, GeneReviews

Senior Director, Laboratory Quality Assurance
Perkin-Elmer Genomics, Inc
Pittsburgh, Pennsylvania

Publication History

Initial Posting: March 8, 2018.

Copyright

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Publisher

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NLM Citation

Wallace SE, Bean LJH. Resources for Genetics Professionals — Genes with Highly Homologous Gene Family Members or a Pseudogene(s) 2018 Mar 8. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

Table.

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

Gene ¹	Homologous Genes and Pseudogenes	Disorder Caused by Pathogenic Variants in this Gene ²	Proportion 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 pseudogenes	ALG1-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 pseudogenes	Nestor-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 pseudogenes	Takenouchi-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 pseudogenes	Breast cancer susceptibility (OMIM 114480)	<5%
CHEK2	≥5 pseudogenes	Prostate cancer susceptibility (OMIM 176807)	<5%
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 pseudogenes	Thrombocytopenia, 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
DCLRE1C ⁷	DCLRE1CP1	SCID Athabaskan (OMIM 602450)	100%
DDX11	≥6 pseudogenes	Warsaw breakage syndrome	100%
DHFR	≥4 pseudogenes	Megaloblastic anemia due to dihydrofolate reductase deficiency (OMIM 613839)	100%
DIS3L2	DIS3L2P1	Perlman syndrome (OMIM 267000)	100%
DPY19L2	≥5 pseudogenes	Globozoospermia, spermatogenic failure (OMIM 613958)	100%
EIF4E	≥5 pseudogenes	Autism (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-filaminopathy	100%
		Myofibrillar myopathy (OMIM 609524)	3%
GBA1 (GBA) ⁸	GBA1LP (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%
HBB	HBBP1	Beta-thalassemia	100%
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 pseudogenes	Hypomyelinating leukodystrophy (OMIM 612233)	2 individuals
HSPD1	≥23 pseudogenes	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%
KRT16	≥5 pseudogenes	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%
NOTCH2	NOTCH2P1	Hajdu-Cheney syndrome (OMIM 102500)	100%
OCLN	LOC647859	Band-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 pseudogenes	Hemolytic 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].

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

Table.

References

Literature Cited

Suggested Reading

Publication Details

Author Information and Affiliations

Publication History

Copyright

Publisher

NLM Citation

Table.