The genetic architecture of thyroid and parathyroid disease underlies susceptibility to congenital hypothyroidism, thyroid hormone resistance, central hypothyroidism, pituitary hormone deficiencies, disorders of calcium homeostasis, and endocrine tumor predisposition. Germline testing across these pathways provides clinicians with a precise understanding of the molecular mechanisms driving both neoplastic and non-neoplastic endocrine syndromes, enabling earlier diagnosis, refined etiologic classification (e.g., dyshormonogenesis vs autoimmune disease vs central causes), optimized surveillance, rational surgical planning, and long-term management of affected patients and at-risk relatives.
PreCheck Health Services’ Thyroid & Parathyroid Disorders Panel (41 genes) is an advanced targeted exome assay encompassing key genes involved in thyroid hormone synthesis and transport, thyroid development and transcriptional control, pituitary–thyroid axis and combined pituitary hormone deficiency, parathyroid development and calcium-sensing pathways, and endocrine tumor susceptibility genes relevant to thyroid and parathyroid neoplasia. The panel is curated using evidence from ACMG, ClinGen, OMIM, GeneReviews, and current peer-reviewed literature, enabling the identification of clinically actionable germline variants that directly inform diagnostic clarification, risk stratification, surgical and medical treatment decisions, and cascade testing within families.
This assay is designed for patients presenting with or at risk for:
❖ Congenital or early-onset hypothyroidism, especially with goiter, thyroid dysgenesis, or suspected dyshormonogenesis
❖ Central hypothyroidism or combined pituitary hormone deficiency with abnormal TSH/FT4 patterns, growth delay, or multiple pituitary hormone deficits
❖ Suspected thyroid hormone resistance or unexplained discordance between thyroid function tests and clinical status
❖ Recurrent, multifocal, or early-onset thyroid carcinoma (including medullary, papillary, and follicular subtypes), particularly with a family history of thyroid cancer or endocrine neoplasia
❖ Primary hyperparathyroidism with multigland disease, recurrent or refractory hypercalcemia, or onset at a young age
❖ Hypercalcemia with low urinary calcium excretion or suspected familial hypocalciuric hypercalcemia / neonatal severe hyperparathyroidism
❖ Patients undergoing thyroid or parathyroid surgery in whom germline results could influence the extent of surgery, margin strategy, or long-term surveillance
This Thyroid & Parathyroid Disorders Panel encompasses key genes involved in thyroid hormone biosynthesis and transport, thyroid and pituitary development, hypothalamic–pituitary–thyroid (HPT) axis regulation, parathyroid development and calcium sensing, and hereditary endocrine neoplasia. Genes are organized into major biological and clinical pathways relevant to congenital and acquired thyroid/parathyroid disease, including congenital hypothyroidism, central hypothyroidism, thyroid hormone resistance, familial hyper- and hypocalcemic states, and inherited endocrine tumor syndromes.
1.Thyroid Hormone Biosynthesis, Iodide Handling, and Organification
Genes involved in iodide uptake, apical iodide transport, hormone synthesis, thyroglobulin processing, and selenoprotein-dependent thyroid hormone metabolism:
❖ TG, TPO, DUOX2, DUOXA2, SLC5A5, IYD, SLC26A4, SECISBP2
2.Thyroid Development, Morphogenesis, and Transcriptional Control
Genes encoding transcription factors and regulators essential for thyroid organogenesis, migration, and structural integrity, frequently implicated in thyroid dysgenesis and syndromic congenital hypothyroidism:
❖ NKX2-1, PAX8, FOXE1, GLIS3
3.Hypothalamic–Pituitary–Thyroid Axis and Central Hypothyroidism
Genes governing hypothalamic TRH production, pituitary development, TSH biosynthesis, pituitary responsiveness to hypothalamic and peripheral signals, and transcriptional control of anterior pituitary hormones, associated with isolated or combined pituitary hormone deficiencies and central hypothyroidism:
❖ HESX1, LHX3, LHX4, PROP1, POU1F1, IGSF1, IRS4, SOX3, TRHR, TSHB, TBL1X
4.Thyroid Hormone Transport, Receptor Signaling, and Hormone Resistance
Genes responsible for cellular transport of thyroid hormone and nuclear receptor-mediated signaling, underlying disorders such as MCT8 deficiency and thyroid hormone resistance syndromes:
❖ SLC16A2, THRA, THRB, TSHR, GNAS
5.Parathyroid Development, Calcium-Sensing, and PTH Resistance
Genes regulating parathyroid gland development, extracellular calcium sensing, and downstream G-protein–mediated signaling, associated with familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, hypocalcemia, hypoparathyroidism, and pseudohypoparathyroidism:
❖ CASR, AP2S1, GNA11, GCM2, GNAS
6.Hereditary Endocrine Neoplasia and Tumor Predisposition Affecting Thyroid and Parathyroid Glands
Genes conferring susceptibility to medullary and non-medullary thyroid carcinoma, primary hyperparathyroidism (including multigland disease and parathyroid carcinoma), and broader hereditary endocrine tumor syndromes (e.g., MEN1/MEN2, PTEN hamartoma tumor syndrome, Carney complex, DICER1 syndrome), as well as moderate- to high-penetrance cancer predisposition impacting thyroid risk:
❖ RET, MEN1, CDC73, PTEN, PRKAR1A, APC, DICER1, TP53, CHEK2, GNAS
Genes Analyzed 41 Hereditary Thyroid & Parathyroid-related genes.
Technology Platform Illumina NGS (Hybrid-Capture Target Enrichment).
Coverage Metrics >98% bases at ≥20× read depth.
Variant Types Detected SNVs and small indels (≤20 bp) within coding exons ±10 bp intronic boundaries.
Reference Genome GRCh38/hg38.
Bioinformatics Pipeline SeqOne™, ACMG/AMP compliant.
Confirmatory Testing Sanger sequencing or orthogonal method as indicated.
Turnaround Time ~10 calendar days.
Quality Metrics Read quality ≥Q30; allelic balance ≥0.3; minimum coverage 20×.
1.Congenital and Early-Onset Thyroid Dysfunction
❖ Clarify the etiology of congenital and childhood-onset hypothyroidism
❖ Distinguish primary thyroid gland failure from hypothalamic–pituitary defects
❖ Support early, tailored levothyroxine (± liothyronine) therapy and long-term follow-up
2.Central Hypothyroidism, Pituitary Disorders, and Atypical Thyroid Function Tests
❖ Define molecular causes of central hypothyroidism and combined pituitary hormone deficiencies to guide imaging, dynamic testing, and hormone replacement strategy.
❖ Resolve discordant thyroid function tests by identifying thyroid hormone resistance
❖ Prevent misdiagnosis and inappropriate dose escalation
3.Thyroid Nodular Disease, Hereditary Thyroid Carcinoma, and Endocrine Neoplasia
❖ Identify germline predisposition to medullary and non-medullary thyroid carcinoma, DICER1-related multinodular disease, and syndromic thyroid involvement
❖ Inform extent and timing of thyroidectomy, lymph node dissection, and prophylactic surgery
❖ Establish individualized ultrasound and biochemical surveillance protocols
4.Parathyroid Disorders and Calcium Homeostasis
❖ Differentiate familial hypocalciuric hypercalcemia from primary hyperparathyroidism to avoid unnecessary surgery and select appropriate medical management.
❖ Diagnose genetic causes of neonatal severe hyperparathyroidism, hypocalcemia, and familial hypoparathyroidism or PTH resistance.
❖ Guide monitoring and treatment to protect bone health, renal function, and long-term homeostasis.
5.Family Counseling, Cascade Testing, and Longitudinal Endocrine Care
❖ Enable targeted testing of relatives once a pathogenic or likely pathogenic variant is identified
❖ Support reproductive counseling, early screening, and preventive interventions
❖ Integrate germline results with biochemical data, imaging, and clinical history to build durable, patient-centered care plans for endocrine and surgical teams.
Thyroid & Parathyroid Disorders testing provides clinically actionable information across endocrinology, pediatrics, internal medicine, endocrine surgery, and clinical genetics, directly influencing diagnosis, risk assessment, surveillance, and treatment strategies.
Risk Stratification and Diagnostic Clarification Identify pathogenic or likely pathogenic variants underlying congenital hypothyroidism, central hypothyroidism, thyroid hormone resistance, familial hyper- and hypocalcemic syndromes, and hereditary thyroid/parathyroid neoplasia.
Family Risk Assessment, Cascade Testing, and Reproductive Counseling
Clarify recurrence risk in families, identify at-risk relatives, and support targeted cascade testing once a familial variant is known, early surveillance in gene-positive but asymptomatic individuals, informed reproductive planning, including options such as prenatal or preimplantation genetic testing when appropriate.
Treatment Selection, Surgical Planning, and Therapeutic Optimization
Use genotype to refine medical and surgical decision-making, including timing and extent of thyroidectomy and lymph node dissection in RET-positive medullary thyroid carcinoma and other hereditary thyroid cancer syndromes, avoidance of unnecessary parathyroid surgery in mediated familial hypocalciuric hypercalcemia, and tailoring of thyroid hormone replacement strategies in transport or receptor defects and structured management of central hypothyroidism and combined pituitary hormone deficiency.
Integrated Longitudinal Endocrine Care
Support multidisciplinary teams (endocrinology, endocrine surgery, pediatrics, genetics, primary care) in building unified, gene-informed care plans that coordinates imaging, laboratory monitoring, and surgical timing over the patient’s lifespan, adapt as guidelines, evidence, and variant classifications evolve, and provide a durable framework for managing complex, multi-gland endocrine syndromes within families.
This Thyroid & Parathyroid Panel is best used as part of a multi-dimensional diagnostic strategy, often in combination with:
Pharmacogenetics Testing (for drug metabolism and gene-drug interactions)
❖ Match treatments to the patient’s metabolic phenotype (e.g., CYP2D6, CYP2C19, CYP3A5, CYP2C9), reducing the risk of adverse drug reactions and improving efficacy.
Together, these tools enable precision medicine teams to offer a fully customized, data-driven treatment plan for each patient.
Germline testing for thyroid and parathyroid disorders is now a critical component of precision endocrine care, allowing clinicians to define the molecular basis of congenital hypothyroidism, central hypothyroidism, thyroid hormone resistance, calcium homeostasis disorders, and hereditary endocrine neoplasia with far greater resolution than clinical and biochemical assessment alone. With a rigorously curated gene panel, high analytic performance, and clinically validated interpretation, PreCheck Health Services provides the genomic insights necessary to refine diagnosis, guide thyroid and parathyroid surgery, individualize hormone replacement and surveillance, and support cascade testing and reproductive counseling. This integrated approach enables earlier, more precise, and more preventive management across the full spectrum of hereditary and familial thyroid and parathyroid conditions.
The Thyroid & Parathyroid gene panel is designed to detect single-nucleotide variants (SNVs) and small insertions and deletions in 41 genes associated with thyroid/parathyroid dysfunction. Targeted regions for this panel include the coding exons and 10 bp intronic sequences immediately to the exon-intron boundary of each coding exon in each of these genes. Extracted patient DNA is prepared using targeted hybrid capture, assignment of a unique index, and sequencing via Illumina sequencing by synthesis (SBS) technology. Data is aligned using the human genome build GRCh38. Variant interpretation is performed according to current American College of Medical Genetics and Genomics (ACMG) professional guidelines for the interpretation of germline sequence variants using Pipeline SeqOne.
AP2S1, APC, CASR, CDC73, CHEK2, DICER1, DUOX2, DUOXA2, FOXE1, GCM2, GLIS3, GNA11, GNAS, HESX1, IGSF1, IRS4, IYD, LHX3, LHX4, MEN1, NKX2-1, PAX8, POU1F1, PRKAR1A, PROP1, PTEN, RET, SECISBP2, SLC16A2, SLC26A4, SLC5A5, SOX3, TBL1X, TG, THRA, THRB, TP53, TPO, TRHR, TSHB, TSHR
This test aims to detect all clinically relevant variants within the coding regions of the genes evaluated. Pathogenic and likely pathogenic variants detected in these genes should be confirmed by orthogonal methods. Detected genetic variants classified as benign, likely benign, or of uncertain significance are not included in this report. Homopolymer regions and regions outside of the coding regions cannot be captured by the standard NGS target enrichment protocols. Currently, the assay does not detect large deletions and duplications. This analysis also cannot detect pathogenic variants within regions that were not analyzed (e.g., introns, promoter and enhancer regions, long repeat regions, and mitochondrial sequence). This assay is not designed to detect mosaicism and is not designed to detect complex gene rearrangements or genomic aneuploidy events. It is important to understand that there may be variants in these genes undetectable using current technology. Additionally, there may be genes associated with thyroid/parathyroid pathology whose clinical association has not yet been definitively established. The test may therefore not detect all variants associated with thyroid/parathyroid pathology. The interpretation of variants is based on our current understanding of the genes in this panel and is based on current ACMG professional guidelines for the interpretation of germline sequence variants. Interpretations may change over time as more information about the genes in this panel becomes available. Qualified health care providers should be aware that future reclassifications of genetic variants can occur as ACMG guidelines are updated. Factors influencing the quantity and quality of extracted DNA include, but are not limited to, collection technique, the amount of buccal epithelial cells obtained, the patient’s oral hygiene, and the presence of dietary or microbial sources of nucleic acids and nucleases, as well as other interfering substances and matrix-dependent influences. PCR inhibitors, extraneous DNA, and nucleic acid-degrading enzymes may adversely affect assay results.
This laboratory-developed test (LDT) was developed, and its performance characteristics were determined by PreCheck Health Services, Inc. This test was performed at PreCheck Health Services, Inc. (CLIA ID: 10D2210020 and CAP ID: 9101993), which is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) as qualified to perform high complexity testing.
This assay has not been cleared or approved by the U.S. Food and Drug Administration (FDA). Clearance or approval by the FDA is not required for the clinical use of this analytically and clinically validated laboratory-developed test. This assay has been developed for clinical purposes, and it should not be regarded as investigational or for research.
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