Mutations in the genes for thyroglobulin and thyroid peroxidase cause thyroid dyshormonogenesis and autosomal-recessive intellectual disability.
We have used single-nucleotide polymorphism microarray genotyping and homozygosity-by-descent (HBD) mapping followed by Sanger sequencing or whole-exome sequencing (WES) to identify causative mutations in three consanguineous families with intellectual disability (ID) related to thyroid dyshormonogenesis (TDH). One family was found to have a shared HBD region of 12.1 Mb on 8q24.21-q24.23 containing 36 coding genes, including the thyroglobulin gene, TG. Sanger sequencing of TG identified a homozygous nonsense mutation Arg2336*, which segregated with the phenotype in the family. A second family showed several HBD regions, including 6.0 Mb on 2p25.3-p25.2. WES identified a homozygous nonsense mutation, Glu596*, in the thyroid peroxidase gene, TPO. WES of a mother/father/proband trio from a third family revealed a homozygous missense mutation, Arg412His, in TPO. Mutations in TG and TPO are very rarely associated with ID, mainly because TDH is generally detectable and treatable. However, in populations where resources for screening and detection are limited, and especially where consanguineous marriages are common, mutations in genes involved in thyroid function may also be causes of ID, and as TPO and TG mutations are the most common genetic causes of TDH, these are also likely to be relatively common causes of ID.
Molecular Neuropsychiatry and Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Kirti
K
Mittal
Molecular Neuropsychiatry and Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Muhammad A
MA
Rafiq
Department of Human Molecular Genetics, Im Neueheimerfeld 366, Heidelberg, Germany.
Rafiullah
R
Rafiullah
Molecular Neuropsychiatry and Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Ricardo
R
Harripaul
Department of Psychiatry, Bolan Medical College, Quetta, Pakistan.
Hazrat
H
Ali
Lahore Institute of Research and Development, Lahore, Pakistan.
Muhammad
M
Ayaz
Lahore Institute of Research and Development, Lahore, Pakistan.
Muhammad
M
Aslam
Lahore Institute of Research and Development, Lahore, Pakistan.|Department of Psychiatry, Queen's University, Kingston, Ontario, Canada.
Farooq
F
Naeem
Department of Zoology, University of Education, Lahore, Pakistan.
Muhammad
M
Amin-Ud-Din
Department of Biochemistry, Quaid-I-Azam University, and Pakistan Medical Research Council, Islamabad, Pakistan.
Ahmed
A
Waqas
Department of Neuroscience Research, CAMH, Toronto, Ontario, Canada.|The Fred A Litwin and Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Joyce
J
So
Department of Human Molecular Genetics, Im Neueheimerfeld 366, Heidelberg, Germany.
Gudrun A
GA
Rappold
Molecular Neuropsychiatry and Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
John B
JB
Vincent
Lahore Institute of Research and Development, Lahore, Pakistan.|Department of Psychiatry, Queen's University, Kingston, Ontario, Canada.
Muhammad
M
Ayub
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D003409:Congenital Hypothyroidism / Q000175:diagnosis* / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D007453:Iodide Peroxidase / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D013954:Thyroglobulin / Q000235:genetics*
D013954:Thyroglobulin; D007453:Iodide Peroxidase