Compendium of causative genes and their encoded proteins for common monogenic disorders

Tucker L Apgar; Charles R Sanders

doi:10.1002/pro.4183

. 2021 Sep 21;31(1):75–91. doi: 10.1002/pro.4183

Compendium of causative genes and their encoded proteins for common monogenic disorders

Tucker L Apgar ¹, Charles R Sanders ^1,^✉

PMCID: PMC8740837 PMID: 34515378

Abstract

A compendium is presented of inherited monogenic disorders that have a prevalence of >1:20,000 in the human population, along with their causative genes and encoded proteins. “Simple” monogenic diseases are those for which the clinical features are caused by mutations impacting a single gene, usually in a manner that alters the sequence of the encoded protein. Of course, for a given “monogenic disorder”, there is sometimes more than one potential disease gene, mutations in any one of which is sufficient to cause phenotypes of that disorder. Disease‐causing mutations for monogenic disorders are usually passed on from generation to generation in a Mendelian fashion, and originate from spontaneous (de novo) germline founder mutations. In the past monogenic disorders have often been written off as targets for drug discovery because they sometimes are assumed to be rare disorders, for which the meager projected financial payoff of drug discovery and development has discouraged investment. However, not all monogenic diseases are rare. Here, we report that that currently available data identifies 72 disorders with a prevalence of at least 1 in 20,000 humans. For each, we tabulate the gene(s) for which mutations cause the spectrum of phenotypes associated with that disorder. We also identify the gene and protein that most commonly causes each disease. 34 of these disorders are caused exclusively by mutations in only a single gene and encoded protein.

Keywords: diseases, disorders, genes, genetic, inherited, Mendelian, monogenic, mutations, proteins, rare

1. INTRODUCTION

As recently as the early‐1980s there were only a handful of heritable human genetic disorders for which the causative mutated gene and its encoded protein were clearly identified. ¹ However, since then a series of advances have led to the identification of hundreds of thousands of disease‐causing gene mutations (http://www.hgmd.cf.ac.uk/ac/stats.php), each one of which is sufficient to cause one of the roughly 7000 known human disorders that exhibit Mendelian inheritance patterns. ² ^, ³ ^, ⁴ This astounding progress provides the basis for unraveling the molecular mechanisms underlying each disorder as well as for the rational development of therapeutics that address the molecular defect(s) that result from each gene mutation. ⁵ Most often, disease mutations encode either a point mutation in a protein or truncation of a protein's sequence. ⁶ This can result in full or partial loss of function for that protein, dysregulated function, inappropriate gain or loss of interactions with other biomolecules, and/or toxicity caused by formation of aggregates, amyloid, or other nonnative forms. The simplicity of the genotype–phenotype relationship for inherited monogenic disorders distinguished these diseases from complex disorders caused by multiple factors as well as from diseases that are caused by noninherited mutations that initially occur in single somatic (nongermline) cells, such as many forms of cancer. ⁷ ^, ⁸ ^, ⁹ ^, ¹⁰

Progress in translating knowledge of the genetic basis for monogenic disorders into therapeutic discovery and development has been hindered by a perception that monogenic disorders usually are rare, ¹¹ ^, ¹² in which case the enormous expenditures typically required to successfully develop a drug and then navigate it through the requisite regulatory approval process may not be recouped by income that eventually derives from marketing that drug. ¹³ ^, ¹⁴ Fortunately, this dire assessment does not extend to all Mendelian disorders, as exemplified by the recent and successful completion of efforts to develop profitable drugs that are effective in treating the most common phenotype of cystic fibrosis (CF, afflicting 1:13,000 people), offering patients—for the first time—the realistic hope of a near‐normal life span. ¹⁵ ^, ¹⁶ These CF drugs address both the mistrafficking and dysfunction of the ΔF508 mutant form of the cystic fibrosis transmembrane regulator chloride channel, which causes the form of the disease shared by 90% of patients.

1.1. Compilation of a compendium of common inherited human diseases

In considering how to assess drug discovery opportunities provided by the current genetic databases for inherited disease we found that there is no well‐curated published compilation of the most common genetic diseases that also provides information regarding which genes and their associated proteins are mutated to cause these disorders. We therefore undertook such a compilation by mining the now‐extensive information available in the literature and from various genetics/disease data depositories. Among the latter, a 2020 report published on‐line by ORPHANET—https://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf—was particularly useful for its up‐to‐date disease prevalence data for inherited and other rare diseases. ¹⁷ ^, ¹⁸ We extracted the list of all human disorders from OPHANET that are known to have a prevalence of >5 people in 100,000 (1:20,000 or higher). We then excluded from the list all those disorders that do not include monogenic forms that exhibit >1:20,000 prevalence. This includes many disorders caused by immune system dysfunction or other nongenetic mechanisms. Also excluded were complex (multi‐factorial) disorders such as type II diabetes, and diseases such as Alzheimer's, ¹⁹ Parkinson's, ²⁰ and hypothyroidism, ²¹ where the etiology of the most common forms of that disorder do not have a simple monogenic origin and the inherited phenotypes are more rare than 1:20,000. Also excluded are the many disorders that are caused mainly by structural changes in the genome, which usually results in gene duplications or deletions, often for multiple genes. Finally, because the ORPHANET report does not actually include the most common monogenic disorders (those not classified as “rare”, such as hypercholesterolemia) we also completed a search to ensure that these were included in our tabulation.

For each monogenic disorder we then conducted searches of a variety of databases (ORPHANET, OMIM, GRAD, PubMed, and GeneReview ²² ^, ²³ ^, ²⁴ ^, ²⁵ ^, ²⁶ ) to identify the gene or genes for which mutations cause that disorder. For each disease‐causative gene we then used UNIPROT ²⁷ to identify the encoded protein. The number of known disease‐causing missense or nonsense mutations that impact the sequence or length of each encoded protein was usually estimated from the “Professional” version of Human Gene Mutation Database (HGMD), ²⁸ except for disorders where literature searches identified additional mutations not yet logged into HGMD. This process led to the compendium in Table 1. For each gene we also tabulated how many different nonsense and missense mutations located in that gene's protein open reading frame are known to be disease‐causing.

TABLE 1.

Compendium of the known >1:20,000 human monogenic disorders and their causative genes and encoded proteins as of mid‐2021

ORPHA‐NET #	Disease or group of diseases	Prevalence (per 100,000) ^a ^, ^b	Mode of inheritance ^c	Known causative genes	Majority gene (with # of causative nonsense/mis‐sense mutations)	Encoded protein name	UNIPROT number	Protein class	% cases caused by majority gene	References
90,794	Adrenal hyperplasia due to 21‐hydroxylase deficiency (21‐OHD CAH)	7.0	Recessive	CYP21A2	CYP21A2 (196)	Cytochrome P450 family 21 subfamily A member 2	P08686	Enzyme	100%	45, 46, 47, 48, 49
51	Aicardi‐Goutières syndrome encephalopathy	10.0*	Recessive	ADAR; IFIH1; RNASEH2A; RNASEH2B; RNASEH2C; SAMHD1; TREX1	RNASEH2B (28)	Ribonuclease H2 subunit B	Q5TBB1	Enzyme	36%	50, 51
60	Alpha‐1‐antitrypsin (A1AT) deficiency (AATD)	20.0*	Recessive	SERPINA1	SERPINA1 (83)	Serpin family A member 1	P01009	Enzyme inhibitor	100%	52, 53
247	Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC, ARVD)	20.0	Dominant or recessive	13 different genes linked to this disorder, so far.	PKP2 (138)	Plakophilin 2	Q99959	Adhesion protein in junctions and intermediate filaments.	34%–74%	54
730	Autosomal dominant polycystic kidney disease (ADPKD)	39.6*	Dominant	BICC1; GANAB; PKD1; PKD2	PKD1 (1154)	Polycystin 1	P98161	Subunit of ion channel complex	78%	55
130	Brugada syndrome ventricular fibrillation	20.0*	Dominant	22 different genes linked to this disorder, so far	SCN5A (725)	Sodium voltage‐gated channel alpha subunit 5	Q14524	Ion channel	15–30%	56, 57
3,286	Catecholaminergic polymorphic ventricular tachycardia (CPVT)	10.0*	Dominant	CALM1; CALM2; CALM3; CASQ2; RYR2; TECRL; TRDN	RYR2 (288)	Ryanodine receptor 2	Q92736	Ion channel	55%	58, 59
166	Charcot–Marie‐Tooth ^d disease/Hereditary motor and sensory neuropathy	40.0*	Dominant, recessive or X‐linked	75 different genes linked to this disorder, so far.	PMP22 (63)	Peripheral myelin protein 22 ^d	Q01453	Ill‐defined role in myelin and Schwann cells	79%	³⁴^,³⁶^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴
418	Congenital adrenal hyperplasia (CAH)	10.0, 6.7 (BP)	Recessive	CYP11B1; CYP17A1; CYP21A2; HSD3B2; POR; STAR	CYP21A2 (214)	Cytochrome P450 family 21 subfamily A member 2	P08686	Enzyme	95–99%	46, 47
35,122	Congenital sucrase‐isomaltase deficiency (CSID)	20.0*	Recessive	SI	SI (23)	Sucrase‐isomaltase	P14410	Enzyme	100%	65, 66
48	Congenital bilateral absence of vas deferens	50.0*	Recessive	CFTR; ADGRG2	CFTR (120)	Cystic fibrosis transmembrane conductance regulator	Q20BH0	Ion channel	78%	67
586	Cystic fibrosis	7.4*	Recessive	CFTR; CLCA4; DCTN4; STX1A; TGFB1	CFTR (1053)	Cystic fibrosis transmembrane conductance regulator	Q20BH0	Ion channel	100%	15, 16, 68
214	Cystinuria‐lysinuria syndrome/Cystinuria	14.0	Recessive	SLC3A1; SLC7A9	SLC7A9 (83)	Solute carrier family 7 member 9	P82251	Membrane transporter	53.00%	69, 70, 71
95,702	Cytomegalic congenital adrenal hypoplasia (AHC) (subtype of congenital adrenal hypoplasia)	8.0	X‐linked	NR0B1	NR0B1 (112)	Nuclear receptor subfamily 0 group B member 1	P51843	Nuclear receptor	100%	72
49,042	Dentinogenesis imperfecta (DGI) (all types)	14.5*	Dominant	DSPP	DSPP (11)	Dentin sialophospho‐protein	Q9NZW4	Seeds biomineral‐ization, Dentinogenesis	100%	73, 74
98,896	Duchenne muscular dystrophy (DMD)	15.1* (BP)	X‐linked	DMD; LTBP4	DMD (830)	Dystrophin	P11532	Structural protein	100%	75, 76
412	Dysbetalipoproteinemia/Hyperliproteinemia type 3	10.0	Recessive	APOE	APOE (42)	Apolipoprotein E	P02649	Lipid carrier, lipoprotein	100%	77
287	Ehlers‐Danlos syndrome	12.5*	Dominant	COL1A1; COL5A1; COL5A2	COL5A1 (106)	Collagen type V alpha 1 chain, collagen type V alpha 2 chain	P20908, P05997	Structural protein	75–78%	78, 79, 80
733	Familial adenomatous polyposis (FAP)	6.0*	Dominant	APC; MUTYH	APC (539)	Adenomatous polyposis coli protein	P25054	Tumor suppressor, regulatory protein	70%	81, 82, 83, 84, 85
79,665	Gardner syndrome (subtype of familial adenomatous polyposis)	9.1 (BP)	Dominant	APC	APC (539)	Adenomatous polyposis coli protein	P25054	Tumor suppressor, associated with microtublules	100%	81
221,061	Familial cerebral cavernous malformation	15.0	Dominant	CCM2; KRIT1; PDCD10	KRIT1 (80)	Krev interaction trapped protein 1	O00522	Regulatory protein	53%	86, 87, 88, 89, 90, 91, 92, 93
93,372	Familial hypocalciuric hypercalcemia type 1 (FHH)	5.5	Dominant	CASR	CASR (373)	Calcium sensing receptor	P41180	G protein‐coupled receptor	100%	94, 95
No entry	Famililal hypercholesterolemia	400.0	Dominant	APOB; LDLR; LDLRAP1; PCSK	LDLR (1254)	Low density lipoprotein receptor	P01130	Lipoprotein receptor	60–80%	96, 97
154	Familial isolated dilated cardiomyopathy	17.5*	Dominant (most often) or X‐linked	45 different genes linked to this disorder, so far.	TTN (672)	Titin	Q8WZ42	Muscle protein	25%	98, 99
768	Familial long QT syndrome (LQTS), including Romano‐Ward syndrome	40.0*	Dominant (most often) or recessive	19 different genes linked to this disorder, so far.	KCNQ1 (448)	Potassium voltage‐gated channel subfamily Q member 1	P51787	Ion Channel	50%	37, 100, 101, 102
908	Fragile X syndrome/Martin‐bell syndrome	32.5	X‐linked	FMR1	FMR1 (7)	Fragile X mental retardation 1	Q06787	Regulator of mRNA biology	100%	103, 104
No entry	Glucose‐6‐phosphate dehydrogenase deficiency	5,000	X‐linked	G6PD	G6PD (218)	Glucose‐6‐phosphate 1 dehydrogenase	P11413	Enzyme	100%	105
79,201	Glycogen storage disease	10.0	Recessive	27 different genes linked to this disorder, so far.	AGL (117)	Glycogen debranching enzyme	P35573	Enzyme	25%	106
309,152	GM2 gangliosidosis	5.0*	Recessive	GM2A; HEXA; HEXB	HEXA (124)	Hexosaminidase subunit alpha	P06865	Enzyme	73%	107, 108, 109, 110
220,489	Hemochromatosis	500	Dominant or recessive	BMP6; HAMP; HFE; HJV; SLC40A1; TFR2	HFE (43)	Hereditary hemochromatosis protein	Q30201	Binds transferrin receptor	85–90%	111
766	Hemolytic anemia due to red cell pyruvate kinase deficiency	5.0*	Recessive	PKLR	PKLR (237)	Pyruvate kinase	P30613	Enzyme	100%	112, 113
448	Hemophilia A and B	7.7*	X‐linked	F8; F9	F8 (1898)	Coagulation factor VIII	P00451	Cofactor for factor IXa	80%	114, 115, 116
98,878	Hemophilia A	11.25 (BP)	X‐linked	F8	F8 (3364)	Coagulation factor VIII	P00451	Cofactor for factor IXa	100%	114, 115, 116
774	Hemorrhagic telangiectasia/Osler Weder Rendu disease	16.0*	Dominant	ACVRL1; ENG; GDF2; SMAD4	ENG (187)	Endoglin	P17813	Regulation of angiogenesis	35%	117, 118, 119, 120
91,378	Hereditary angioedema (HAE)/Angioneurotic edema	5.0*	Dominant	ANGPT1; F12; PLG; SERPING1	SERPING1 (252)	Serpin family G member 1	P05155	Enzyme inhibitor	95%	121
145	Hereditary breast and ovarian cancer syndrome	25*	Dominant	14 different genes linked to this disorder so far.	BRCA1 (1262)	Breast cancer type 1 susceptibility protein	P38398	E3 ubiquitin‐protein ligase	~66%	122
469	Hereditary fructose intolerance/Fructosemia	5.0*	Recessive	ALDOB	ALDOB (32)	Aldolase, fructose‐bisphosphate B	P05062	Enzyme	100%	123
3,467	Hereditary xanthinuria/Xanthine stone disease	9.05* (I)	Recessive	MOCOS; XDH	MOCOS (8); XDH (17)	Molybdenum cofactor sulfurase, xanthine dehydrogenase	Q9C5X8, P47989	Enzymes	MOCOS and XCH cause 100%, but relative contributions not yet known	124
238,468	Hypohidrotic ectodermal dysplasia (HED)	6.7*	X‐linked	10 different genes linked to this disorder, so far.	EDA (199)	Ectodysplasin A	Q92838	Cytokine	65–75%	125, 126, 127, 128, 129, 130, 131, 132
42,062	Iminoglycinuria	6.68*	Recessive	SLC36A2; SLC6A18; SLC6A19; SLC6A20	SLC36A2 (1)	Solute carrier family 36 member 2	Q495M3	Membrane transporter	100%	133
524	Li‐Fraumeni syndrome sarcoma, breast, leukemia, and adrenal gland (SBLA) syndrome	6.0	Dominant	CDKN2A; CHEK2; MDM2; TP53	TP53 (417)	Tumor protein p53	P04637	Tumor suppressor, gene regulation	91%	134
5	Long chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency (LCHAD)	8.0*	Recessive	HADHA	HADHA (35)	Hydroxyacyl‐CoA dehydrogenase trifunctional multienzyme complex subunit alpha	P40939	Enzyme	100%	135
144	Lynch syndrome	125	Dominant	11 different genes linked to this disorder so far	MSH2 (34)	DNA mismatch repair protein Msh2	P43246	DNA repair, binds DNA, ATPase	20–40%	136
558	Marfan syndrome	15.0	Dominant	FBN1; TGFBR2	FBN1 (1893)	Fibrillin 1	P35555	Structural protein, extracellular matrix	90%	137, 138, 139
2,209	Maternal phenylketonuria/Phenylketonuric embryopathy	10.0* (I)	Recessive	PAH	PAH (690)	Phenylalanine hydroxylase	P00439	Enzyme	100%	140
42	Medium chain acyl‐CoA dehydrogenase deficiency (MCADD)	6.85, 12.0*	Recessive	ACADM	ACADM (136)	Acyl‐CoA dehydrogenase medium chain	P11310	Enzyme	100%	141
423,461	Mucolipidosis type III (ML3) alpha/beta	13.0	Recessive	GNPTAB	GNPTAB (68)	N‐acetylglucosamine 1 phosphate transferase, Subunits alpha and beta	Q3T906	Enzyme	100%	142
309,297	Mucopolysaccharidosis type 4A (MPS4A)/Morquio disease type A	15.0*	Recessive	GALNS	GALNS (269)	Galactosamine (N‐acetyl)‐6‐sulfatase	P34059	Enzyme	100%	143
653	Multiple endocrine neoplasia type 2	7	Dominant	RET	RET (130)	Ret proto‐oncogene receptor tyrosine kinase	P07949	Receptor tyrosine kinase	100%	144
251	Multiple epiphyseal dysplasia (MED)	5.0*	Dominant (most often) or recessive	COL2A1; COL9A1; COL9A2; COL9A3/collagen type IX alpha 3 chain; COMP; KIF7; MATN3; SLC26A2	COMP (155)	Cartilage oligomeric matrix protein	P49747	Structural protein	81–87%	145, 146, 147, 148
636	Neurofibromatosis type 1 (NF1)/Von Recklinghausen disease	21.3*, 33.3	Dominant	NF1	NF1 (1208)	Neurofibromin 1	P21359	Regulator of Ras GTPase activity	100%	149
55	Oculocutaneous albinism (OCA)	5.9	Recessive	LRMDA; MC1R; OCA2; SLC24A5; SLC45A2; TYR; TYRP1	TYR (352)	Tyrosinase	P14679	Enzyme	50%	150, 151, 152, 153
666	Osteogenesis imperfecta/brittle bone disease	10.0*	Dominant	15 different genes linked to this disorder, so far.	COL1A1 (547); COL1A2 (466)	Collagen type I alpha 1 chain, collagen type I alpha 2 chain	P02452, P08123	Structural protein	85–90%	154, 155, 156, 157
705	Pendred syndrome (PDS)/Deafness with goiter	7.0*	Recessive	FOXI1; KCNJ10; SLC26A4	SLC26A4 (404)	Solute carrier family 26 member 4	O43511	Membrane transporter	90%	158, 159, 160, 161, 162, 163, 164, 165, 166
716	Phenylketonuria (PKU)/Phenylalanine hydroxylase deficiency (PAH deficiency)	10.0*	Recessive	PAH	PAH (690)	Phenylalanine hydroxylase	P00439	Enzyme	100%	167
70	Proximal spinal muscular atrophy (SMA)	20.0*	Recessive	NAIP; SMN1; SMN2	SMN1 (47)	Survival motor neuron protein	Q16637	RNA splicing	~100%	168, 169, 170, 171, 172, 173, 174, 175
791	Retinitis Pigmentosa (RP)	26.7	Dominant (most often), recessive or X‐linked	82 different genes linked to this disorder, so far.	RHO (204)	Rhodopsin	P08100	G‐protein coupled receptor	20–30% autosomal dominant (15%–25% of total cases)	176, 177, 178, 179
461	Recessive X‐linked ichthyosis (XLI)	16.6*	X‐linked	STS	STS (28)	Steroid sulfatase	P08842	Enzyme	100%	180
790	Retinoblastoma (RB bilateral (40% of cases) and unilateral (60% of cases—de novo mutation)	6.0	Dominant	NMYC; RB1	RB1 (292)	RB transcriptional corepressor 1	P06400	Tumor suppressor, cell cycle regulation	98%	181
778	Rett syndrome	10.0*	X‐linked	MECP2	MECP2 (246)	Methyl‐CpG binding protein 2	P51608	Binds to methylated DNA, gene regulation	90–95%	182, 183, 184
232	Sickle cell anemia	10.0*	Recessive	HBB	HBB (433)	Hemoglobin subunit beta	P68871	Oxygen carrier	100%	185
821	Sotos syndrome/cerebral gigantism	7.1	Dominant	APC2; NSD1; SETD2	NSD1 (228)	Nuclear receptor binding SET domain protein 1	Q96L73	Enzyme	95%	186, 187, 188, 189, 190
827	Stargardt disease/Fundus flavimaculatus	13.0*	Recessive	ABCA4; CNGB3; ELOVL4; PROM1; PRPH2	ABCA4 (789)	ATP binding cassette subfamily A member 4	P78363	Membrane transporter	95%	191, 192, 193
828	Stickler syndrome/ hereditary progressive arthroophthalmopathy	12.2	Dominant (most often) or recessive	COL11A1; COL2A1; COL11A2; COL9A1; COL9A2; COL9A3; LOXL3	COL2A1 (335)	Collagen type II alpha 1 chain	P02458	Structural protein	80–90%	194, 195, 196
3,193	Supravalvular aortic stenosis (SVAS)	13.3*	Dominant	ELN	ELN (25)	Elastin	P15502	Structural protien	100%	197
848	β‐Thalassemia	1,500	Dominant or recessive	HBB	HBB (434)	Hemoglobin B chain	P68871	Oxygen carrier	100%	198
609	Tibial muscular dystrophy/Upp myopathy	6.0*	Dominant	TTN	TTN (53)	Titin	Q8WZ42	Muscle protein	100%	199
805	Tuberous sclerosis complex/Bourneville syndrome	10.0*	Dominant	TSC1; TSC2	TSC2 (518)	Tuberin	P49815	Tumor suppressor, Regulation of mTORC1 signaling	69%	200, 201, 202, 203, 204, 205
892	Von‐Hippel Lindau disease	6	Dominant	VHL	VHL (218)	Von Hippel–Lindau tumor suppressor	P40337	Tumor suppressor, role in E3 ubiquitin ligase complex	100%	206
903	Von Willebrand disease	12.5	Dominant (most often) or recessive	VWF	VWF (636)	Von Willebrand factor	P04275	Collagen binding, chaperone for coagulation factor VIII	100%	207
43	X‐linked adrenoleukodystrophy (ALD)	5.0	X‐linked	ABCD1	ABCD1 (425)	ATP binding cassette subfamily D member 1	P33897	Membrane transporter	100%	208
792	X‐linked retinoschisis (XLRS)	5.0	X‐linked	RS1	RS1 (203)	Retinoschisin 1	O15537	Membrane binding, cell–cell adhesion	100%	209

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^{^a}

Value listed is prevalence unless otherwise indicated as “BP” (birth prevalence) or “I” (incidence). Prevalence is a measure of how many people in the population suffer from a given disorder. Birth prevalence is a measure of how many people are born with the disorder already manifest. Incidence is a measure of how many people will develop the disorder during their lifetime (symptoms for many genetic disorders appear only later in life and/or are progressive).

^{^b}

An asterix associated with the prevalence value means this value was determined based on a Western European population, the reference population used by ORPHANET when there was insufficient data to estimate prevalence across the entire human race.

^{^c}

For most common form.

^{^d}

For Charcot–Marie–Tooth disease and related peripheral neuropathies, roughly 55% of cases are caused by the presence of a third wild type allele encoding the peripheral myelin protein 22 (PMP22) protein ²¹⁰ ^, ²¹¹ and 20% of cases are caused by loss of one of the normal two wild type alleles. Much more rare forms are caused by mutations that either truncate the PMP22 sequence or introduce single amino acid replacements. ²¹² Mutations impacting any one of another roughly 75 other genes result in the remaining ca. 25% of cases of Charcot–Marie‐Tooth.

There are 72 diseases or families of closely related diseases in our database of common genetic disorders (Table 1). Before we survey this database, it is important to state a major limitation. The prevalence data list in Table 1 is the best available for each disorder as of the time that the 2020 ORPHANET report was compiled. However, prevalence values are often skewed relative to the entire human population by the genetic profile of the specific human sub‐population sampled to determine the prevalence of each disorder. ²⁹ ^, ³⁰ ^, ³¹ ^, ³² In particular, a majority of the prevalence values in the ORPHANET report are based on the genetic profile of the Western European population. ¹⁷ These Euro‐centric prevalence values are flagged in the original ORPHANET compilation and here in Table 1 by affixing an asterisk to the reported value. We regret that we cannot rule out that there may be diseases missing from this table that are common in ethnic groups that are highly underrepresented in the currently available genetic datasets. The identities of the most commonly causative gene and protein for some disorders could also be influenced by ethnicity‐related sample bias. This is critically important since factors related to genetic ancestry influences susceptibility to disease, as well as health outcomes. Therefore, Table 1 must regarded as an evolving “working compilation”, subject to ongoing revisions and updates.

1.2. The common (>1:20,000) monogenic disorders and their causative genes and proteins

We conclude with a few observations about the data in Table 1. First, for 34 of the tabulated monogenic disorders—nearly half—mutations in only a single gene and its encoded protein are known to cause 100% of all cases of that disease. From the standpoint of attempting to therapeutically target all clinical forms of a given disorder with a uniform approach, these single‐causative‐gene‐only monogenic disorders are likely to be the easiest to target. However, it should be recognized that even when there is only a single causative gene, there is always a spectrum of disease mutations in that gene, each of which causes its own clinical features. ³³ ^, ³⁴ The exact nature and severity of each clinical form can vary greatly depending on the details of how each specific mutation impacts the encoded protein. ⁷ ^, ³⁵ ^, ³⁶ For example, mutations in the KCNQ1 potassium channel cause type 1 long QT syndrome (LQTS1). Recent work has shown that the most common classes of LQTS1‐causing mutations destabilize the channel, leading to misfolding, mistrafficking, and degradation—resulting in channel loss of function. However, more rare LQTS1 mutations do not significantly impact the folding of the channel, but lead to loss or dysregulation of function through other mechanisms. ³⁷

For all of the “majority genes” listed in Table 1 there are multiple known disease‐causing mutations, with the total number varying from 11 to >1000. This variation can reflect the amount of research to date devoted for each disease (intensely studied diseases are more likely to yield the identities of their more rare causative mutations than less‐studied diseases), the size of the gene (long genes have a greater number of possible mutations), and also the molecular mechanism(s) that lead to disease pathogenesis. ³⁸ For example, diseases caused by loss of function due to mutation‐induced misfolding often exhibit a spectrum of mutations at sites that are distributed fairly evenly over the full length of the protein, whereas mutations that alter the “active sites” of enzymes, transporters, or channels may be more focused around the specific domains of the protein that embody those sites. ³⁴

In terms of what functional classes of majority gene‐encoded proteins are represented in Table 1, there is a wide range, but 20 are enzymes, 11 are ion channels or membrane transporters, and nine are structural/fibrillar/muscle proteins. That enzymes are the most common functional class in this Table echoes both their numerically high representation in the human proteome ³⁹ and their prominence as the most common class of proteins targeted by currently approved drugs. ⁴⁰ ^, ⁴¹ However, it is interesting that even though G protein‐coupled receptors are the targets for about 30% of all drugs ⁴⁰ ^, ⁴² the only GPCRs appearing on this list are the photoreceptor of vision, rhodopsin, and the calcium‐sensing receptor.

The inheritance pattern associated with each disease often provides clues about disease mechanism. ⁴³ Recessive disorders are typically caused by the potentially complete loss of function that occurs when both alleles encoding a given protein are subject to a loss of function mutation. Dominant disorders may be caused by the up to 50% loss of function that results from WT/mutant heterozygosity. However, dominance can also reflect either that the mutated protein interacts with the wild type protein in a way that unfavorably interferes with the native WT function or that the mutated protein is actively toxic (often referred to as “toxic gain of function”). ⁶ X‐linked disorders usually affect men more severely—sometimes exclusively—because the mutated X chromosome gene will be present in all of their cells, whereas for women some cells will express the wild type form of the gene while the other cells will express the disease mutant. ⁴⁴

Finally, while we have not conducted a detailed analysis of the current state of therapeutics development for each disease listed in Table 1, many of these disorders are serious and currently have no effective treatment, much less a cure. Moreover, even for those where there are therapeutic approaches, available treatments sometimes do not address the underlying defects in the mutated protein(s) that cause the disease. As noted, cystic fibrosis provides an exception, where 30 years of intense research and development has led to an effective set of drugs that target the molecular basis for the disease. It is hoped that this compendium may prove useful to those looking either to establish new projects focused on proteins of direct disease relevance or to initiate drug discovery efforts that target relatively common diseases with a clear genotype–phenotype relationships.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

AUTHOR CONTRIBUTIONS

Tucker L. Apgar: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (supporting). Charles R. Sanders: Conceptualization (equal); formal analysis (equal); investigation (equal); methodology (equal); project administration (equal); resources (equal); supervision (equal); writing – original draft (lead).

ACKNOWLEDGMENTS

We acknowledge the support of US NIH grants R01 HL122010, R01 NS095899, and RF1 AG056147. Partial support for Tucker L. Apgar was provided by an Vanderbilt University Summer Research Program award. We also thank Professors Alfred George (Northwestern University Feinberg School of Medicine), Jamaine Davis (Meharry Medical College), and Roy Zent (Vanderbilt University Medicine Center) for their useful comments and suggestions related to this manuscript.

Apgar TL, Sanders CR. Compendium of causative genes and their encoded proteins for common monogenic disorders. Protein Science. 2022;31:75–91. 10.1002/pro.4183

Funding information National Heart, Lung, and Blood Institute, Grant/Award Number: R01 HL122010; National Institute of Neurological Disorders and Stroke, Grant/Award Number: R01 NS095899; National Institute on Aging, Grant/Award Number: RF1 AG056147; US NIH, Grant/Award Numbers: RF1 AG056147, R01 NS095899, R01 HL122010

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PERMALINK

Compendium of causative genes and their encoded proteins for common monogenic disorders

Tucker L Apgar

Charles R Sanders

Abstract

1. INTRODUCTION

1.1. Compilation of a compendium of common inherited human diseases

TABLE 1.

1.2. The common (>1:20,000) monogenic disorders and their causative genes and proteins

CONFLICT OF INTEREST

AUTHOR CONTRIBUTIONS

ACKNOWLEDGMENTS

REFERENCES

ACTIONS

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RESOURCES

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PERMALINK

Compendium of causative genes and their encoded proteins for common monogenic disorders

Tucker L Apgar

Charles R Sanders

Abstract

1. INTRODUCTION

1.1. Compilation of a compendium of common inherited human diseases

TABLE 1.

1.2. The common (>1:20,000) monogenic disorders and their causative genes and proteins

CONFLICT OF INTEREST

AUTHOR CONTRIBUTIONS

ACKNOWLEDGMENTS

REFERENCES

ACTIONS

PERMALINK

RESOURCES

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