Table 7.

Genes and chromosomal loci linked to non-syndromic familial non-medullary thyroid cancer

Gene	Chromosome	Study details	Reference
MAP2K5	15q23	34 families with two first-degree relatives with PTC (no syndromic FNMTC). Whole exome and target gene sequencing for candidate variants.	Ye et al. (2019) [86]
PLCB1	20p12.3	Genome wide linkage analysis and next generation sequencing performed in a family with MNG that was likely to progress to PTC as seen in some family members. An intronic PLCB1 InDel was found in all affected members.	Bakhsh et al. (2018) [87]
BROX	1q41	Whole-exome sequencing of PTC patients from five families. Two BROX variants were observed in two of the families.	Pasquali et al. (2021) [88]
POT1	7q31.33	Whole exome sequencing of five affected family members with melanoma and thyroid cancer revealed a new mutation in POT1. POT1 is involved with the telomere shelterin complex that controls telomere protection.	Wilson et al. (2017) [89]
		A low frequency variant in POT1 was found in childhood cancer survivors that developed thyroid cancer.	Richard et al. (2020) [90]
		A POT1 variant causes telomere dysfunction in a family affected only by FNMTC.	Srivastava et al. (2020) [91]
ATM	11q22.3	Whole-genome sequencing and genome-wide linkage analysis in 17 FNMTC families. ATM variant was identified in two families.	Wang et al. (2019) [92]
CHEK2	22q12.1	Whole-genome sequencing and genome-wide linkage analysis in 17 FNMTC families. A CHEK2 (breast and prostate cancer susceptibility gene) variant was identified in one family.	Wang et al. (2019) [92]
NOP53	19q13.33	Exome sequencing in a family with five cases of NSFNMTC and 44 additional families with FNMTC showed a low-penetrance germline variant of NOP53 with increased levels in tumour samples of the affected cases.	Orois et al. (2019) [93]
NDUFA13/ GRIM-19	19p13.11	A germline mutation was found in a patient with Hurthle cell PTC. No Grim-19 mutations were observed in familial Hurthle cell tumours. GRIM-19 is involved in mitochondrial metabolism.	Máximo et al. (2005) [94]
TIMM44	19p13.2	Screening of 14 candidate genes in the linkage region of affected TCO members from 8 FNMTC families. TIMM44 is a mitochondrial inner membrane translocase.	Bonora et al. (2006) [95]
SRRM2	16p13.3	Whole exome sequencing in a PTC family with six affected first- or second-degree relatives detected a germline variant in SRRM2. This gene is involved in RNA splicing, with aberrant alternative splicing in affected individuals.	Tomsic et al. (2015) [96]
ANXA3	4q21.21	Whole exome sequencing in three Brazilian families with familial PTC yielded seven new genes with implication in hereditary PTC.	Sarquis et al. (2020) [97]
NTN4	12q22
SERPINA1	14q32.13
FKBP10	17q21.2
PLEKHG5	1p36.31
P2RX5	17p13.2
SAPCD1	6p21.33
Unknown	8q24 (PTCSC1)	Genome wide linkage analysis in a large family with PTC and melanoma.	He et al. (2009) [98]
Unknown	4q32	Linkage analysis and targeted deep sequencing identified an ultra-rare mutation (SNP) in chromosome 4q32 in a large pedigree affected by FNMTC.	He et al. (2013) [99]
Unknown	6q22	Linkage analysis in 38 FNMTC families revealed, 6q22 (Maximum LOD of 3.3) displayed linkage.	Suh et al. (2009) [100]
Unknown	1q21 (fPTC,PRN)	Linkage analysis in a large three-generation familial PTC kindred, maximum LOD of + 3.58.	Malchoff et al. 2000) [101]
		Linkage analysis in forty-nine affected cases with FNMTC, maximum LOD of + 3.04.	Suh et al. (2009) [100]
Unknown	14q32 (MNG1)	Linkage analysis in a Canadian family with 18 cases of MNG (2 of which were also diagnosed with PTC). Maximum LOD of 3.8.	Bignell et al. (1997) [102]
Unknown	2q21 (NMTC1)	Linkage analysis in a large Tasmanian pedigree with PTC. Multipoint heterogeneity LOD of 3.07.	Mckay et al. (2001) [103]
		Linkage analysis in 10 FNMTC families. Linkage evident at both TCO and NMTC (LOD = 1.56 and 2.85, respectively)	Mckay et al. (2004) [104]
		Loss of heterozygosity (LOH) was analyzed at 2q21 and 19p13.2 in 9 FNMTC families. Two of the fourteen tumours displayed LOH at 2q21 (14%).	Prazeres et al. (2008) [105]
Unknown	8p23.1-p22 (FTEN)	Linkage analysis in a Portuguese family affected by PTC and benign thyroid lesions detected a linkage with 8p23.1-p22, Maximum haplotype-based LOD of 4.41.	Cavaco et al. (2008) [106]
Unknown	19q13.2 (TCO)	Linkage analysis in a French pedigree affected by PTC and MNG lead to mapping chromosome 19p13.2 to TCO (thyroid tumours with cell oxyphilia). Maximum LOD of 3.01.	Canzian et al. (1998) [107]
		Linkage analysis in one family with PTC and MNG. Maximum LOD of 1.54.	Bevan et al. (2001) [108]
		Linkage analysis in ten families affected by PTC and MNG. Maximum LOD of 1.56.	McKay et al. (2004) [104]
		Loss of heterozygosity (LOH) was analyzed at 19p13.2 in 9 FNMTC families. Eight of the fourteen tumours displayed LOH at 19p13.2 (57%).	Prazeres et al. (2008) [105]