ESPE Abstracts (2016) 86 FC11.3

aPediatric Endocrinology, Diabetology and Gynecology Department, Necker Enfants-Malades University Hospital, AP-HP, Paris, France; bIMAGINE Institute, Paris, France; cCochin Institute, INSERM U1016, Faculty of Medicine, Paris Descartes University, Sorbonne Paris Cité, Paris, France; dHistology, Embryology and Cytogenetics Department, Necker Enfants-Malades University Hospital, AP-HP, Paris Descartes University, Paris, France; eGenetics Department, INSERM U955, Henri Mondor Hospital, AP-HP, Paris-Est University, Paris, France; fBioinformatics Platform, Paris Descartes University, IMAGINE Institute, Paris, France; gGenomics Platform, INSERM U1163, Paris Descartes University, IMAGINE Institute, Paris, France; hTranslational Genetics Unit, INSERM U1163, IMAGINE Institute, Paris Descartes University, Paris, France

Background: Brain-Lung-Thyroid (BLT) syndrome (OMIM# 610978) is characterized by congenital hypothyroidism (CH), infant respiratory distress syndrome (IRDS), and benign hereditary chorea and is caused by thyroid transcription factor 1 (NKX2-1/TTF1) haploinsufficiency. The phenotype can be partial or complete and there is a large phenotypic variability.

Objectives and hypotheses: Identify new genes in a selected group of patients presenting thyroid, brain and/or lung dysfunction, but without NKX2-1 abnormalities.

Methods: From a well-characterised cohort of patients (Carré et al, Hum Mol Genet 2009) with thyroid disorders associated with brain and/or lung symptoms, we selected 8 patients negative for NKX2-1 mutations. Array Comparative Genomic Hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) analysis were performed to detect any DNA copy number variations (CNV) and NKX2-1 deletion respectively. Whole exome sequencing was performed using the kit Agilent SureSelectXT Human All Exon V6 on Illumina HiSeq 2500 HT, with a trio analysis (proband and parents) strategy.

Results: The complete triad was present in two patients. Thyroid disorders presented as CH (n=7) or subclinical hypothyroidism (n=1) and concerned gland in situ (n=3) and athyreosis (n=5). The majority of patients had neurological impairment (6/8 patients, 75%), mainly as ataxia (n=3) and neonatal hypotonia (n=2). Developmental delay was the major finding in one patient. Lung disease as IRDS was present in four patients. No CNVs were identified in chromosome 14 and close to region 14q13. MLPA did not reveal any anomaly. WES has already been realised in five trios (n=15) and two index cases and revealed new candidate genes involved in the pathogenesis of the disease.

Conclusion: In this well-described cohort on clinical and molecular level, WES allowed to identify candidate genes. Genetic heterogeneity was demonstrated with several genes explaining the clinical phenotype and expanding our knowledge about the syndrome.

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