Genetics

Peter Kopp

DEFINITION

Genetic components contribute to virtually all disorders, with the exception of simple trauma. Many chromosomal and monogenic disorders can now be explained at the molecular level, permitting to establish the diagnosis by mutational analysis (for selected examples, see Table 12.1) [1, 12, 13, 14, 15, 16, 19]. It is important to recognize that genetic and environmental modifiers may also strongly influence the phenotype in monogenic disorders, which simply present the least complex form in a continuum [7]. For example, siblings with identical mutations in the transcription factor PROP1, which lead to combined pituitary hormone deficiency (CPHD) [22], may have variable constellations of anterior pituitary hormone deficiencies, and the onset of the hormonal defects may differ [20]. In phenylketonuria, the development of the neurologic defects is dependent on the amount of phenylalanine in the diet. In complex disorders, also referred to as polygenic or multifactorial disorders, several or multiple genes contribute to the pathogenesis, typically in conjunction with environmental and lifestyle factors such as in diabetes mellitus type 2 (Chapter 6) [4, 7, 10, 51, 52, 54]. Genetic analyses are now greatly facilitated by the increasingly dense information about the human genome gleaned from the Human Genome Project (HGP) [7, 13]. A first draft had been completed in 2000, and the HGP announced the completion of the DNA sequence for the last of the human chromosomes in 2006. The Personal Genome Project now aims at sequencing the genomes from multiple individuals and to associate them with health and physical data in order to obtain further insights into the genetic basis of human (patho)physiology. These developments are paralleled by fast-paced advances in next-generation sequencing technologies. It is anticipated that sequencing of the whole human genome of a human individual for a cost of $1,000 or less will become a reality within the next few years [9, 81, 82]. In addition to sequencing genomic DNA for the detection of mutations and variants, next-generation sequencing technologies can be used, among other applications, for the analysis of RNA expression and epigenetic modifications of the genome [82].

The HGP and the HapMap Project also facilitate the study of complex disorders [7]. The HapMap project has determined single nucleotide polymorphisms

(SNPs), variants that occur on average every 300 base pairs (bp) throughout the genome, in DNA samples from multiple individuals from several different ethnic backgrounds. Adjacent SNPs are inherited together as blocks, referred to as haplotypes, hence the name HapMap. These blocks can be identified by selected marker SNPs, so-called tag SNPs. The availability of this information permits to characterize a limited number of SNPs in order to determine the set of haplotypes present in an individual, for example, in cases and controls. This information has a significant impact on genome-wide association studies (GWAS), which search for associations of certain SNPs and haplotypes with complex disorders.

Table 12.1. Molecular Basis of Selected Endocrine Disorders

Disorder/Phenotype	Chromosomal Defect		OMIM
*Chromosomal disorders with endocrine manifestations*
Turner syndrome: Ovarian failure, short stature, autoimmune thyroid disease	45,XO
Klinefelter syndrome: Hypogonadism, tall stature	47,XXY
Prader-Willi syndrome: Short stature, obesity, hypogonadism	del15 q11-13 (Paternal copy) or Maternal uniparental disomy		176270
Disorder/Phenotype	Gene	Inheritance	OMIM
*Hypothalamic and pituitary disorders*
CPHD (GH, PRL, TSH, LH, FSH)	PROP1	AR	601538
Short stature	GH	AR,AD	139250
Neurohypophyseal diabetes insipidus	AVP-NPII	AD,AR	192340
Obesity	Leptin receptor	AR	601007
*Thyroid*
Congenital hypothyroidism with thyroid hypoplasia	PAX8	AD	167415
Bamforth-Lazarus syndrome:	TTF2 (FOXE1)	AR	602617
Congenital hypothyroidism, cleft palate, spiky hair
Pendred syndrome: Sensorineural deafness, impaired iodide organification	PDS (SLC26A4)	AR	274600
Congenital hypothyroidism, TG defects	TG	AR	188450
Resistance to thyroid hormone	THRB	AD, (AR)	190160
*Parathyroid and bone disorders*
Familial benign hypocalciuric hypercalcemia	CASR	AD	601199
Familial hypoparathyroidism	CASR	AD	601199
Albright hereditary osteodystrophy	GNAS1	AD	103580
*Adrenal gland*
Congenital adrenal hyperplasia, 21-hydroxlyase	CYP21	AR	201910
Glucocorticoid-remediable aldosteronism	CYP11B2-CYP11B1 fusion gene	AD	103900
Adrenal hypoplasia congenital, hypogonadism	DAX1 (NROB1)	X	300473
*Pancreas*
MODY 1	HNF4α	AD	125850
MODY 2	GCK	AD (inactivating mutations)	125851
MODY 3	HNF1α	AD	600496
MODY 4, renal cysts	IPF1	AD	606392
MODY 5	HNF1β	AD	604284
MODY 6	NEUROD1	AD	606394
Pancreas agenesis	IPF1	AR	600733
*Gonads*
Androgen insensitivity, AR inactivation	AR	AR	300068
Androgen insensitivity, 5α-reductase deficiency	SRD5A2	AR	607306
Aromatase deficiency, female genitalia with masculinization during puberty	CYP19A1	AR	107910
*Water and salt metabolism*
Nephrogenic diabetes insipidus (X-linked form)	AVPR2	X	304800
Nephrogenic diabetes insipidus	AQP2	AR,AD	107777
Liddle syndrome: Hypokalemic metabolic acidosis, hypertension	SCNN1B or SCNN1G	AD	177200
*Lipid metabolism*
Obesity	LEP	Leptin	164160
Familial hypercholesterinemia	LDLR	AD	606945
*Tumor syndromes*
Multiple endocrine neoplasia 1: Parathyroid adenoma, pituitary adenoma, pancreas tumors	MEN1	AD	131100
Multiple endocrine neoplasia 2: (A) Medullary thyroid cancer, pheochromocytoma, parathyroid hyperplasia. (B) + ganglioneuromas	RET	AD	171400
von Hippel-Lindau disease: Renal carcinomas, pheochromocytomas, other tumors	VHL	AD	193300
Pheochromocytoma/Paraganglioma	MEN1, MEN2 NF1, VHL SDHB, SDHC, SDHD	AD or sporadic	131100, 171400 162200, 193300 185470, 602413, 602690
	TMEM127		613403
*Somatic mosaicism*
McCune-Albright syndrome: Precocious puberty, fibrous dysplasia, café-au-lait spots, hyperthyroidism	GNAS1	Mosaic somatic mutation acquired in early development	174800
*Complex syndromes*
Autoimmune polyglandular syndrome type 1:	AIRE	AR	240300
Adrenal insufficiency, hypoparathyroidism, candidiasis
Disorder/Phenotype	Genes/Loci		OMIM
*Complex disorders*
Diabetes mellitus type 1	HLA DR3/4-DQ201/0302, HLA DR4/4-DQ0300/03022, HLA DR3/3-DQ0201/0201 INS, PTPN22, IL2RA, CTLA4, IFIH1		222100
	Multiple others
Diabetes mellitus type 2	PPARG, KCNJ11, TCF7L2 IGF2BP2, CDKAL1, SLC30A8, CDKN2A/B, JJEX, FTO, HNF1B		125853
	Multiple others
Note: This list only contains selected examples. In addition, the reader should be aware that the same or similar phenotype can be caused by mutations in other genes.
AD, autosomal dominant; AR, autosomal recessive; X, X-chromosomal; CPHD, combined pituitary hormone deficiency.
Modified from Kopp P. genetics, genomics, proteomics, and bioinformatics. In: Brook GD, Brown R (eds). Clinical Pediatric Endocrinology, 5th ed. Oxford. Blackwell Science; 205; 18-44, 2005. With permission.

More recent insights into the structure of the human genome reveal a high degree of complexity. For example, certain regions of the genome, often containing numerous genes, can be duplicated once or even be present in multiple copies. These copy number variations (CNVs) tend to vary in a specific manner among different populations and are associated with hot spots of chromosomal rearrangements [11]. CNVs are thought to contribute to normal human variation as well as to disease through alterations in the dosage of a single gene or a set of contiguous genes.

Somatic mutations, that is, mutations that are limited to the affected tissue, in genes controlling cell growth, survival, and differentiation are key elements in the pathogenesis of benign and malignant tumors [7, 13]. Moreover, many cancers are associated with a predisposition conferred by hereditary germline mutations. The multiple endocrine neoplasia syndromes 1 and 2 (MEN1 and MEN2) are excellent examples to illustrate this (Table 12.1) [67]. MEN2 also highlights the impact of genetic analysis for carrier detection in the clinical management of families with this tumor syndrome (Chapter 9) [67]. A thorough understanding of the molecular pathogenesis of cancer is also of paramount importance for the development of novel therapeutic modalities. For example, the mutations in the tyrosine kinase RET causing MEN2 [67], or the serine-threonine kinase B-Raf found frequently in papillary thyroid cancers, make them attractive targets for therapy with kinase inhibitors [68, 86], a paradigm shown to be successful in chronic myelogenous leukemia by the specific inhibition of the Bcr-Abl tyrosine kinase through imatinib [63].

Numerous endocrine disorders have been elucidated at the molecular level [12, 13, 14, 15, 16, 19]. For comprehensive overviews, and for the discussion of the principles of human genetics, DNA structure, and molecular biology analyses, which are beyond the scope of this chapter, the reader is referred to several comprehensive reviews and text books [7, 13, 15, 80].

Genetic and genomic information is a key component of so-called personalized medicine, in which diagnosis, choice of therapy, and preventive measures are tailored to an individual based on differences in the genome [5, 6, 53, 55]. For example, the management of carriers of RET gene mutations in kindreds affected by MEN2 or familial medullary thyroid cancer (FMTC) is, in part, dependent on the specific RET gene mutation, which display variable aggressivity [69].

ETIOLOGY

Mutations in DNA cause alterations and abnormal function in the encoded RNA and protein products, thereby leading to disease [2, 3]. Mutations can occur randomly or through factors such as radiation and chemicals. Mutations occurring in the germline (sperm or oocytes) can be transmitted to progeny. If the germline is mosaic, a mutation can be transmitted to some offspring but not others. Mutations occurring during early development lead to somatic mosaicism, as illustrated by the McCune-Albright syndrome (MAS) [65, 66]. Somatic mutations conferring a growth advantage to cells, or a decrease in apoptosis, can be
associated with neoplasia. Epigenetic alterations, for example, altered DNA methylation, are also frequently found in malignancies and can result in altered gene expression. With the exception of triplet nucleotide repeats [8], which can progressively expand, mutations are usually stable.

Structurally, mutations are extremely diverse [2]. They can involve the entire genome, as in triploidy, or gross numerical or structural alterations in chromosomes or individual genes [7, 13]. Large deletions may affect a part of a gene, an entire gene, or several genes (contiguous gene syndrome). Somatic chromosomal rearrangements are found in many tumors. For example, rearrangements of the RET gene with several other genes can be found in a subset of papillary thyroid carcinomas [70]. Mutations affecting single nucleotides are referred to as point mutations. A mutation in the coding region leading to an amino acid substitution is referred to as missense mutation; a mutation resulting in a stop codon is a nonsense mutation. Small nucleotide deletions or insertions cause a shift of the reading frame (frameshift), and this typically results in an abnormal protein of variable length after the deletion. It is not sufficiently appreciated that mutations also occur in noncoding regions. Mutations in intronic sequences may destroy or create splice donor or splice acceptor sites, and mutations in regulatory sequences result in altered gene transcription.

EPIDEMIOLOGY

The frequency of monogenic disorders is highly variable [2]. Some monogenic disorders are extremely rare. Some recessive disorders occur predominantly in inbred populations or consanguineous matings. One should always consider the possibility of compound heterozygous mutations, that is, distinct mutations in the maternal and paternal copy of the same gene [62, 64]. In many dominant and X-linked disorders, de novo mutations account for a significant fraction of cases. The rates for new mutations for autosomal dominant and X-linked disorders are estimated to be about approximately 10^-5 to 10^-6/locus per generation. Other monogenic disorders are, however, relatively frequent. The classic examples include cystic fibrosis (Northern European populations), the thalassemias (Mediterranean, Southeast Asia), and sickle cell trait/disease (West Africa) [7]. It is generally thought that accumulation of these deleterious alleles in a population is due to a selective advantage in heterozygotes. For example, heterozygotes for the sickle cell mutation have a reduced morbidity and mortality from malaria because their erythrocytes provide a less favorable environment for Plasmodium parasites.

The distribution patterns of different genotypes in a population are the focus of population genetics [7]. If the frequency of an allele is known, and assuming that the population is in a state of equilibrium, the frequency of the genotypes can be determined (Hardy-Weinberg law). This is useful for the calculations of carrier frequencies, disease prevalence, and estimates of penetrance. The equilibrium can be modified by migration, new mutation(s), and genetic drift, that is, random fluctuations in allele frequencies in small populations.

The genetic epidemiology of complex disorders is challenging because of the fact that several or multiple loci may contribute to the phenotype and that it is influenced by multiple gene-gene interactions (also referred to as epistasis) and geneenvironment interactions. In the endocrine field, this is impressively illustrated by our current understanding of the genetics of diabetes mellitus (Chapter 6) [51]. The neonatal and monogenic autosomal dominant forms of diabetes (MODY 1 to 6; maturity onset diabetes of the young) have been elucidated at the molecular level and are caused by severe mutations in genes that are essential for development and/or function of the pancreatic beta cell [50, 53, 55]. These mutations are
relatively rare in the population. In contrast, our knowledge about the genetic basis of diabetes mellitus type 2, although rapidly growing, remains more modest [51]. This may be explained by the difficulty in detecting alleles that are only contributing mildly to the phenotype, and the fact that these alleles are frequent in the general population [4]. Moreover, one should recognize that the clinical diagnosis of diabetes mellitus type 2 may encompass various entities of impaired insulin action and secretion and that the elucidation of the genetic components will require more homogeneous collections of patients.

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Tags: Evidence-Based Endocrinology

Aug 2, 2016 | Posted by drzezo in ENDOCRINOLOGY | Comments Off

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