Table 1.

Germline mutations in familial neuroblastoma predisposition genes. ALK, anaplastic lymphoma kinase; PHOX2B, paired-like homeobox 2B; HPCAL1, Hippocalcin-like protein 1.

Gene	Mutation	Clinical Characteristics	Functional Consequence	Reference
PHOX2B	R100L	Found in families with Hirschsprung disease and neuroblastic tumors	Missense mutation in DNA binding domain Not dominant negative	(Trochet et al. 2004) (Bourdeaut et al. 2005) (Pei et al. 2013)
	R141G	Neuroblastoma patient inherited from mother, who was not affected	Missense mutation in homeodomain	(Trochet et al. 2004)
	G197D	Present in a family with multiple individuals with NB but no evidence of autonomic dysfunction or neurocristopathy		(McConville et al. 2006)
	676delG	Found in families with Hirschsprung disease and neuroblastoma	Overexpression causes decrease in terminal differentiation markers in sympathetic ganglion cells Dominant negative Unable to bind HPCAL1	(Mosse et al. 2004) (Pei et al. 2013) (Wang et al. 2014)
	Polyalanine Repeat Mutations	Associated with congenital central hypoventilation syndrome (CCHS)	Genotype 20/33 identified in a neuroblastoma/CCHS/Hirschsprung disease patient	(Armstrong et al. 2015)
ALK	R1060H	Unlikely to be clinically significant Believed to be a silent/passenger mutation	Not predicted to be damaging by algorithms Between kinase and transmembrane domains	(Bresler et al. 2014)
	G1128A		P-loop of kinase domain Transforms NIH-3T3 cells	(Mosse et al. 2008)
	T1151M T1151R	T1151R found in patient with multifocal tumors	Promotes modest constitutive ALK activation Does not transform NIH-3T3 cells β3 Strand of kinase domain	(Bourdeaut et al. 2012) (Bresler et al. 2014)
	I1183T	Unlikely to be clinically significant Believed to be a silent/passenger mutation	N-lobe of kinase domain	(Bresler et al. 2014)
	R1192P	Found in patient with multifocal tumors	β4 Strand of kinase domain Increases kcat of non-phosphorylated ALK tyrosine kinase domain by 15x Transforms NIH-3T3 cells	(Mosse et al. 2008) (Bourdeaut et al. 2012) (Bresler et al. 2014)
	L1204F	Unlikely to be clinically significant Believed to be a silent/passenger mutation	C-lobe of kinase domain	(Bresler et al. 2014)
	R1231Q	Unlikely to be clinically significant Believed to be a silent/passenger mutation	Not predicted to be damaging by algorithms αE helix of kinase domain	(Bresler et al. 2014)
	I1250T	Unlikely to be clinically significant Believed to be a silent/passenger mutation	“Kinase dead” mutation that results in reduced activity via protein instability/misfolding Phe core domain	(Schonherr, Ruuth, Eriksson, et al. 2011) (Bresler et al. 2014)
	R1275Q	Crizotinib-sensitive Found in patient with multifocal tumors	R1275 residue accounts for ~45% of overall neuroblastoma ALK mutations (sporadic and germline) Activation loop of kinase domain	(Mosse et al. 2008) (Bresler et al. 2011) (Bourdeaut et al. 2012)