Mutations in the thyroglobulin (TG) gene have been reported to cause congenital hypothyroidism (CH) and we have been investigating the genetic architecture of CH in a large cohort of consanguineous/multi-case families. Our aim in this study was to determine the genetic basis of CH in four affected individuals coming from two separate consanguineous families. Since CH is usually inherited in autosomal recessive manner in consanguineous/multi-case families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the TG gene. First we investigated the potential genetic linkage of families to any known CH locus using microsatellite markers and then determined the pathogenic mutations in linked-genes by Sanger sequencing. Both families showed potential linkage to TG locus and we detected two previously unreported nonsense TG mutations (p.Q630X and p.W637X) that segregated with the disease status in both families. This study highlights the importance of molecular genetic studies in the definitive diagnosis and classification of CH, and also adds up to the limited number of nonsense TG mutations in the literature. It also suggests a new clinical testing strategy using next-generation sequencing in all primary CH cases.