Endocrine Genetics

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Endocrine Genetic


Precision in diagnosis, including the identification of disease subtypes, directly influences treatment and patient outcomes. Understanding of pathology at a molecular level is critical for identification of many diseases and their subtypes.

Presenting ACTIA from MedGenome, delivering ACTIONABLE insights to enable happier outcomes. Actia provides an end-to-end integrated solution to clinical genomics in India and is highly focussed on the Indian population.

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Endocrine Genetics

Endocrine diseases span a vast range of conditions. Inherited Endocrine disorders have a defective gene resulting in the body’s over or under-production of certain hormones. Endocrine disorders include hypothyroidism, congenital adrenal hyperplasia etc.

*Shashi V, McConkie-Rosell A, Rosell B, et al. The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders. Genet Med. 2014;16(2):176–82.

Genetics of Endocrine Disorders

Advances in genetic testing have been crucial to discovering the underlying causes of several endocrine disorders. They act as a guide for treatment, as well as for applying preventive measures for other family members. As genome sequencing continues to reveal the functions and dysfunctions of particular genes, genetic tests are better, especially when hormone tests provide ambiguous results. From common health issues like thyroid disease to rare adrenal tumours, these tests can reveal the inheritable component of a person’s condition and can guide the approach to treatment. Early diagnosis and treatment can significantly impact a person’s prognosis. Several molecular testing options are available in MedGenome to help in diagnostic confirmation and risk assessment for family members.

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The common endocrine disorders can now rely on Genetic tests

Congenital hypothyroidism

  • Partial or complete loss of function of the thyroid gland
  • Thyroid dysgenesis is seen in 80 to 85 percent of cases
  • Dyshormonogenesis in remainder of the cases
  • If untreated, can lead to intellectual disability and slow growth
  • Inheritance could be autosomal recessive or dominant
  • The disorder can be syndromic (Pendred syndrome and brain-lung-thyroid syndrome) or non-Syndromic


The involvement of genetic factors is estimated to be 40-70% in obesity

  • Monogenic obesity is severe early-onset obesity, associated with endocrine disorders, mainly due to mutations in obesogenic or leptogenic genes (LEP, LEPR, POMC, PC1, MC4R)
  • Syndromic obesity refers to obesity associated with other genetic syndromes like Prader-Willi and Bardet-Biedl. But more than 100 syndromes are now
  • MedGenome offers a monogenic obesity panel covering majority of single genes as well as syndromic obesity genes.


Diabetes mellitus is an etiologically heterogeneous disorder with Type 1 and 2 diabetes mellitus being multifactorial and polygenic. Neonatal Diabetes mellitus and Maturity-onset diabetes of the young (MODY) are the two main forms of monogenic diabetes.

Maturity-onset diabetes of the young (MODY)

  • Is a monogenic form of diabetes characterized by a primary defect in pancreatic ß-cell function
  • Has an early onset, and an autosomal dominant mode of inheritance
  • Though MODY can occur at any age, it is more likely to affect adolescents and young adults
  • Often misdiagnosed as type 1 or type 2 Diabetes mellitus
  • Till date, at least 13 MODY subtypes with distinct genetic aetiologies have been identified
  • A correct genetic diagnosis is important as it often leads to a personalized treatment for the patient and enables predictive genetic testing for their asymptomatic relatives
  • Next-generation sequencing provides an efficient method for screening mutations in this form of Diabetes as well as identifying new MODY genes


Diabetes occurring under 6 months of age is predominantly monogenic

  • The fraction of cases without a known cause is diminishing rapidly as new genes are discovered
  • The phenotype encapsulates numerous subtypes, wherein most aetiologies involve a severe disruption in ß-cell function
  • Can be permanent and require lifelong treatment, or may be transient, in which case the diabetes may spontaneously remit (or be so mild as not to require treatment), but will often relapse, usually during adolescence

Genetic testing can diagnose most forms of monogenic diabetes. If genetic testing is not performed, people with monogenic diabetes may appear to have one of the polygenic forms of Diabetes. A correct diagnosis allows the proper treatment to be selected and it should lead to better glucose control and improved health in the long term. Testing of other family members may also be indicated to determine whether they are at a higher risk for Diabetes.


Congenital Adrenal Hyperplasia (CAH)

  • Most common DSD
  • CAH are a family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by the adrenal cortex
  • Among all CAH disorders, 21-hydroxylase deficiency (21-OHD) is the most common cause
  • The diagnosis of classic 21-OHD CAH is established in new-borns with characteristic clinical features, elevated serum 17-OHP, and elevated adrenal androgens
  • Sequence analysis of CYP21A2 is performed first followed by gene-targeted deletion/ duplication analysis if only one or no pathogenic variant is found
  • Almost 70%-80% of patients can be detected by sequence analysis while 20%-30% may require gene-targeted deletion/duplication analysis by MLPA
  • To avoid diagnostic errors, studying both parents as well as the proband is recommended to confirm the pathogenic variants and to determine if they are in cis-configuration or trans-configuration

Androgen receptor deficiency second common DSD after CAH

  • The gene encoding androgen receptor (AR) is located on the X chromosome
  • Mutations in AR gene cause androgen insensitivity syndrome (AIS), formerly known as the testicular feminization syndrome (TFM)
  • The androgen insensitivity syndrome is an X-linked recessive disorder in which affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal male 46,XY karyotype
  • Partial androgen insensitivity results in hypospadias and micropenis with gynecomastia (Reifenstein syndrome)
  • Sequence analysis by NGS can detect almost 95%-97% of the patients with AIS
  • Gene targeted deletion/duplication analysis to detect multi-exon or whole-gene deletions or duplications may be considered if a pathogenic variant in AR is not identified by sequence analysis (3-5% of the cases)
  • Medgenome offers MLPA technique for testing Androgen receptor (AR) deletion/ duplication analysis and NSG for AR NGS analysis

Kallmann Syndrome:

  • Characterized by delayed or absent puberty and an impaired sense of smell (hyposmia) or completely absent (anosmia)
  • This feature distinguishes Kallmann syndrome from most other forms of hypogonadotropic hypogonadism, which do not affect the sense of smell
  • Many people with Kallmann syndrome are not aware that they are unable to detect odors discovered through testing
  • More than 20 genes have been associated with Kallmann syndrome, and mutations in the ANOS1, CHD7, FGF8, FGFR1, PROK2 or PROKR2 genes are the most common
  • In some cases, affected individuals have mutations in more than one of these genes. Medgenome offers a gene panel analysis for all the involved genes using NGS

Familial lipid disorders:

  • Patients with lipid disorders have trouble maintaining normal levels of body fats, and these disorders can be found in several conditions that require special management, including metabolic syndrome, polycystic ovary syndrome (PCOS), and obesity. Special diets, exercise, and medications may be prescribed to manage hyperlipidemia and other lipid disorders
  • A familial lipid disorder is a condition that causes very high levels of cholesterol. This condition can lead to early onset coronary artery disease (CAD).

There are different types of lipid disorders. They include:

  1. Familial combined hyperlipidemia (FCHL)
  2. Familial defective apolipoprotein B-100
  3. Familial dysbetalipoproteinemia (type 3 hyperlipoproteinemia)
  4. Familial hypertriglyceridemia
  5. Heterozygous familial hypercholesterolemia

Primary causes of dyslipidemias involve gene mutations that cause the body to produce too much LDL cholesterol or triglycerides, or the failure to remove these substances. Some causes involve underproduction or excessive removal of HDL cholesterol. Primary causes tend to be inherited and thus run in families. Multi-gene panel involving all the associated genes in dyslipidiema are available for genetic testing. MLPA may be required for testing deletion/ duplication in certain genes. For ex. sequence analysis of LDLR is performed first followed by LDLR deletion/duplication analysis if no pathogenic variant is found in the case of Familial Hypercholesterolemia.

Test Methodology

1.Next Generation Sequencing (NGS)

Using genomic DNA extracted from blood, the coding regions of all the genes are captured and sequenced simultaneously by NGS technology on an Illumina platform. The sequence data that is generated is aligned and analyzed for sequence variants.

2.Multiplex ligation-dependent probe amplification (MLPA)

Deletion and duplication analysis of genomic DNA is carried out by MLPA. This method allows for the amplification of multiple targets with only a single primer pair.

Test sample requirements

Test sample requirements
Blood (3-5ml in EDTA tubes)
Extracted DNA samples (1µg high quality DNA)

Required forms

  • Relevant clinical information including all the clinical presentations and symptoms
  • Test request form (TRF)

Turnaround time

  • 4 weeks for NGS
  • 3 weeks for MLPA
  • 3 weeks for Sanger sequencing
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