Screening Chromosomal Aberrations by Array Comparative Genomic Hybridization in 80 Patients with Congenital Hypothyroidism and Thyroid Dysgenesis

• Published in: The journal of clinical endocrinology and metabolism Vol. 95; no. 7; pp. 3446 - 3452
• Main Authors: Thorwarth, A, Mueller, I, Biebermann, H, Ropers, H. H, Grueters, A, Krude, H, Ullmann, R
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.07.2010; Copyright by The Endocrine Society
• Subjects: Biological and medical sciences; Chromosome Aberrations; Comparative Genomic Hybridization; Congenital Hypothyroidism - genetics; DNA Copy Number Variations - genetics; Endocrinopathies; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Gene Duplication; Gene Expression Profiling; Genetic Testing - methods; Humans; Male; Medical sciences; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Segmental Duplications, Genomic - genetics; Thyroid Dysgenesis - genetics; Thyroid. Thyroid axis (diseases); Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Endocrinopathy; Chromosomal aberration; Human; Obesity; Endocrine gland; Congenital; Nutrition; Thyroid diseases; Nutrition disorder; Patient; Metabolic diseases; Thyroid gland; Medical screening; Gene expression; Hypothyroidism; Congenital disease; Comparative genomic hybridization; Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2009-2195

Objective: Congenital hypothyroidism occurs in 1:3500 live births and is therefore the most common congenital endocrine disorder. A spectrum of defective thyroid morphology, termed thyroid dysgenesis (TD), represents 80% of permanent congenital hypothyroidism cases. Although several candidate genes have been implicated in thyroid development, comprehensive screens failed to detect mutation carriers in a significant number of patients with nonsyndromic TD. Due to the sporadic occurrence of TD, de novo chromosomal rearrangements are conceivably representing one of the molecular mechanisms participating in its etiology. Methods: The introduction of array comparative genomic hybridization (CGH) has provided the ability to map DNA copy number variations (CNVs) genome wide with high resolution. We performed an array CGH screen of 80 TD patients to determine the role of CNVs in the etiology of the disease. Results: We identified novel CNVs that have not been described as frequent variations in the healthy population in 8.75% of all patients. These CNVs exclusively affected patients with athyreosis or thyroid hypoplasia and were nonrecurrent, and the regions flanking the CNVs were not enriched for segmental duplications. Conclusions: The high rate of chromosomal changes in TD argues for an involvement of CNVs in the etiology of this disease. Yet the lack of recurrent aberrations suggests that the genetic causes of TD are heterogenous and not restricted to specific genomic hot spots. Thus, future studies may have to shift the focus from singling out specific genes to the identification of deregulated pathways as the underlying cause of the disease. DNA copy number changes identified in congenital hypothyroidism affect genes not previously implicated in the etiology of this disease.