Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy

Fry, Andrew E.; Rees, Elliott; Thompson, Rose; Mantripragada, Kiran; Blake, Penny; Jones, Glyn; Morgan, Sian; Jose, Sian; Mugalaasi, Hood; Archer, Hayley; McCann, Emma; Clarke, Angus; Taylor, Clare; Davies, Sally; Gibbon, Frances; Te Water Naude, Johann; Hartley, Louise; Thomas, Gareth; White, Catharine; Natarajan, Jaya; Thomas, Rhys H.; Drew, Cheney; Chung, Seo-Kyung; Rees, Mark I.; Holmans, Peter; Owen, Michael J.; Kirov, George; Pilz, Daniela T.; Kerr, Michael P.

doi:10.1186/s12881-016-0294-2

Table 2 Rare CNVs detected in 80 patients with ID/DD and epilepsy

From: Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy

Subject	Age	Sex	Clinical features	Seizure onset	Syndrome	Seizure types	Cytoband	CNV Type	Coordinates	Size (Kb)	Tests	Status	Interpretation	Genes
R125	10 m	F	Severe DD, cleft palate	3 m	EIMFS	FE, EBCS, CSE	2q24.3	Del	163823021–167958723	4,136	c/f	DN	Path	SCN3A, SCN2A, SCN1A, SCN9A, SCN7A & 8 others
R351	15y	M	Moderate DD, poor coordination, joint contractures, mildly dysmorphic	3 m	Dravet	FS, GTCS, CSE, M	2q24.3	Del	166842637–166918932	76	c/d	DN	Path	SCN1A
R404	7y	F	Mild DD, ASD	8 m	West	IS, Abs	16p11.2	Del	29595483–30198151	603	b/e,f	DN	Path	DOC2A, KIF22, MAPK3, PRRT2, QPRT, SEZ6L2 & 24 others
R660	21y	M	Mod-severe ID, challenging behaviour, ASD, depression, dysmorphic	8 m	GGE-ID	Abs, M, FDS, EBCS	9q34.3	Del	140707889–140890373	182	b/e	DN	Path	CACNA1B, EHMT1
							3p14.2	Dup	59736299–61023355	1,287	b/e	Pat	Likely	FHIT
							3p22.1	Del	41359533–41824555	465	b/e	Mat	VUS	ULK4
R911	22y	F	Mod ID, small head, mildly dysmorphic	10y	FE	FDS, GTCS	2q22.3	Del	148691873–148818437	127	b/e	DN	Path	MBD5, ORC4
R913	20y	M	Mod-severe ID, challenging behaviour, ASD	10 m	FE	FS, FDS, EBCS	16p13.11	Dup	15512574–16262571	750	b/e	Mat	Likely	ABCC1, C16orf45, FOPNL, KIAA0430, MIR484, MYH11, NDE1
R345	27y	F	Mild ID, dysmorphic	<6y	GGE-ID	M, Abs, GTCS	2q13	Del	111392259–113094793	1,703	b/e	Pat	Likely	BUB1, BCL2L11, ANAPC1, MERTK, FBLN7 & 5 others
R58	26y	F	Severe ID, scoliosis	<8y	GGE-ID	At, Abs, M	1q21.1	Dup	145625979–145723645	98	a/e	Mat	VUS	CD160, RNF115
R74^a	51y	F	Mild-mod ID, depression	3 m	FE	FS, FE, EBCS	1p21.1	Del	104167778–104297867	130	a/e	U	VUS	AMY1A, AMY1B, AMY1C, AMY2A
R101	32y	M	ID, seizures	<16y	U	U	11q22.3	Del	109173027–109325299	152	b/e	Pat	VUS	C11orf87
R198	19y	M	Severe ID, ASD, mild right hemiparesis	7 m	LGS	FE, IS, Abs, NCS, GTCS, At, FDS	Xq28	Del	150589930–150811921	222	c/nd	U	VUS	PASD1
R528	23y	M	Severe ID, challenging behaviour, ASD, dysmorphic, regression	11y	FE	FE, Abs	15q13.3	Dup	32019919–32514341	494	b/e	U	VUS	CHRNA7
R605	41y	M	ID, seizures	<16y	U	U	15q11.2	Dup	22383292–23272733	889	b/e	Pat	VUS	CYFIP1, NIPA1, NIPA2, TUBGCP5 & 8 others
							8p23.1	Del	11713852–12204679	491	b/e	Mat	VUS	CTSB, FAM66D, FAM86B1, USP17L2, ZNF705D & 6 others
R622^a	28y	F	Moderate ID, challenging behaviour	6 m	GGE-ID	IS, GTCS, M	18p11.22	Dup	10042023–10581304	539	b/e	Mat	VUS	APCDD1, NAPG
R650	21y	M	Mild ID, thin habitus, depression	18 m	GGE-ID	Abs, M, GTCS	15q13.3	Dup	32029693–32514926	485	a/nd	U	VUS	CHRNA7
			Mild ID, thin habitus, depression				15q14	Del	34700297–34807869	108	a/nd	U	VUS	GOLGA8A
R786	9y	M	Moderate DD, Leg hypertonia, dystonia	2y	GGE-ID (M)	M, Abs, At	21q21.3	Del	27715263–27955385	240	a/e	Mat	VUS	CYYR1
R931	15y	F	Severe DD, ASD, dysmorphic, microcephaly	12y	GGE-ID	GTCS	7q11.22	Del	71815170–72305671	491	b/e	Pat	VUS	CALN1, MIR4650-1, MIR4650-2, SBDSP1, TYW1B
R981	5y	F	Severe DD, regression, ASD, leg hypertonia	1w	GGE-ID	Abs, At, M, T	3p26.3	Dup	726675-1301830	575	c/nd	U	VUS	CNTN6

Age (at recruitment) and seizure onset in y(ears), m(onths) or w(eeks). Clinical features: ID intellectual disability, DD, developmental delay, ASD autism spectrum disorder
Syndrome, electroclinical syndrome or main epilepsy type at recruitment: Dravet, Dravet syndrome; EIMFS, epilepsy of infancy with migrating focal seizures: FE focal epilepsy, GGE-ID, genetic generalised epilepsy with ID, LGS Lennox-Gastaut syndrome, U unknown, West West syndrome
Seizure types: Abs absence, At atonic, CSE convulsive status epilepticus, EBCS evolution to bilateral or convulsive seizures, FDS focal dyscognitive seizures, FS febrile seizures, GTCS generalised tonic-clonic seizures, IS infantile spasms, M myoclonic, NCS non-convulsive status epilepticus, T tonic, seizure type at presentation is underlined (when known)
CNV type, Dup(lication) or Del(eletion). Coordinates, chromosome position of first/last abnormal probes based on hg19/GRCh37. Tests, primary array/confirmation method: (a) Illumina610-Quad SNP-array, (b) Illumina OmniExpress SNP-array, (c) BlueGnome CytoChip array CGH, (d) quantitative PCR, (e) Illumina Exome BeadChip or custom Illumina SNP array, (f) fluorescence in situ hybridization, and (nd) not done. Status: DN, de novo; inherited Pat(ernally); Mat(ernally) or U(nknown). Interpretation (of clinical significance): Path(ogenic); Likely, likely pathogenic; VUS, variant of uncertain significance
^aPatients R622 and R74 had pathogenic SCN1A mutations which suggests these two CNVs are likely to be benign

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ISSN: 1471-2350

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