Thyroid Biology and Disease

SUN-379 - A Novel Genetic Cause of Familial Medullary Thyroid Carcinoma: Intragenic SLC30A9 Deletion and Translation Reinitiation

Sunday, June 14, 2026

9:00 AM - 4:00 PM CT

Location: ENDOExpo; Poster Floor

Submitting author(s)

Donato Iacovazzo, MD, PhD, FRCPath

NIHR Clinical Lecturer
Queen Mary University of London
London, United Kingdom

Rapid and Poster Presenter(s)

Donato Iacovazzo, MD, PhD, FRCPath

NIHR Clinical Lecturer
Queen Mary University of London
London, United Kingdom

Co-Author(s)

FB

Federica Begalli, n/a

Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London
London, United Kingdom
OS

Oniz Suleyman, n/a

Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London
London, United Kingdom
MD

Márton Doleschall, n/a

Molecular Medicine Research Group, Eötvös Loránd Research Network and Semmelweis University
Budapest, Hungary
KA

Kevin Ashelford, n/a

Division of Cancer and Genetics, Cardiff University School of Medicine
Cardiff, United Kingdom
SA

Sherine Awad Mahmoud, n/a

Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge
Cambridge, United States
SB

Sayka Barry, n/a

Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London
London, United Kingdom
CC

Claudia P. Cabrera, n/a

Centre for Translational Bioinformatics, William Harvey Research Institute, Queen Mary University of London
London, United Kingdom
KC

Kevin Colclough, n/a

Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust
Exeter, United Kingdom
AC

Alexandra Csábi, n/a

Molecular Medicine Research Group, Eötvös Loránd Research Network and Semmelweis University
Budapest, Hungary
JF

Jawid M. Fatih, n/a

Department of Molecular and Human Genetics, Baylor College of Medicine
Houston, Texas, United States
MG

Mira Gandhi, n/a

Department of Molecular and Human Genetics, Baylor College of Medicine
Houston, Texas, United States
CG

Christopher M. Grochowski, n/a

Department of Molecular and Human Genetics, Baylor College of Medicine
Houston, Texas, United States
CH

Charlotte L. Hall, n/a

Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London
London, United Kingdom
KM

Kesson Magid, n/a

Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London
London, United Kingdom
MM

Monika Mozere, n/a

Department of Renal Medicine, University College London
London, United Kingdom
MO

Martina Owens, n/a

Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust
Exeter, United Kingdom
LO

Luka Ozretić, n/a

Department of Cellular Pathology, Royal Free London NHS Foundation Trust
London, United Kingdom
AP

Attila Patócs, n/a

Department of Molecular Genetics and the National Tumour Biology Laboratory, National Institute of Oncology
Budapest, Hungary
JP

Jaya Punetha, n/a

Department of Molecular and Human Genetics, Baylor College of Medicine
Houston, Texas, United States
HS

Horia Stanescu, n/a

Department of Renal Medicine, University College London
London, United Kingdom
MT

Mehmet Tekman, n/a

Department of Renal Medicine, University College London
London, United Kingdom
LT

Laura E. Thomas, n/a

Institute of Life Science 1, Swansea University
Swansea, United Kingdom
CC

Claudia M.B. Carvalho, n/a

Department of Molecular and Human Genetics, Baylor College of Medicine
Houston, Texas, United States
MF

Martin Franke, n/a

Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide
Seville, Spain
RK

Robert Kleta, n/a

Department of Renal Medicine, University College London
London, United Kingdom
JL

James R. Lupski, n/a

Department of Molecular and Human Genetics, Baylor College of Medicine
Houston, Texas, United States
JS

Julian R. Sampson, n/a

Division of Cancer and Genetics, Cardiff University School of Medicine
Cardiff, United Kingdom
LD

Laura De Marinis, Professor

Catholic University of Rome
Rome, Italy

Senior Author/Primary Investigator(s)

MK

Marta Korbonits, MD PhD (she/her/hers)

Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London
London, United Kingdom

Disclosure(s):

Donato Iacovazzo, MD, PhD, FRCPath: No financial relationships to disclose

Introduction: Familial medullary thyroid carcinoma (fMTC) is caused, in most cases, by RET mutations. However, in rare instances, the genetic cause remains unknown. We studied two related families with RET mutation-negative fMTC (confirmed with genome sequencing) in 21 affected individuals across multiple generations and identified a novel disease-causing intragenic SLC30A9 deletion.

Methods: Single nucleotide polymorphism genotyping was performed in all subjects with available DNA to confirm relatedness and allow for linkage analysis. Exome/genome sequencing and high-density array comparative genomic hybridization (HD-aCGH) were undertaken in selected affected individuals. The localization of mutant SLC30A9 protein was investigated with immunofluorescence in HEK293T cells stably expressing mutant SLC30A9. Cycloheximide chase experiments were performed to assess protein stability. The effects of the SLC30A9 intragenic deletion on cell proliferation and clonogenic capacity were investigated in an MTC cell line via lentivirus-mediated expression of the mutant construct.

Results: The two families of Italian ancestry showed an autosomal dominant inheritance pattern with high penetrance and mean age at diagnosis of 22.3 years (range 7-41). Linkage analysis highlighted a region of chromosome 4 with LOD score of 3.93 (28-55 Mb), likely indicating the locus of the causative mutation. Exome and genome sequencing failed to identify pathogenic small variants, while HD-aCGH revealed a heterozygous intragenic deletion of 40,348bp within the linkage region involving exons 2-7 of SLC30A9 (4p13), a gene encoding a zinc transporter relevant for mitochondrial zinc homeostasis. The deletion segregated with the disease in all affected individuals, and prospective screening allowed identification of two further affected subjects who have been successfully treated with surgery. Mutant SLC30A9 mRNA was found to escape degradation, leading to the production of N-terminally truncated proteins via translation reinitiation from AUG codons located downstream of the deletion. These truncated proteins showed increased stability in cycloheximide chase experiments. Unlike wild-type SLC30A9, which localized to mitochondria, truncated SLC30A9 showed dot-like expression which colocalized with endoplasmic reticulum markers, suggesting protein misfolding. Expression of mutant SLC30A9 in an MTC cell line led to increased cell proliferation and clonogenic capacity in colony forming assays, supporting its oncogenic role.

Conclusions: We identified a novel genetic cause of fMTC. Our results expand the genetic background of inheritable MTC beyond RET mutations and implicate translation reinitiation in the etiology of cancer susceptibility syndromes secondary to structural genomic variants.