Table 3.

Details of the variants identified in 11 non‐syndromic NIEE patients

Gene	Case no.	Type of variants	Exon	mRNA accession no.	Variants		Location in protein	ExACa	Reported/Novel	Inheritance patterns	Silico prediction toolsb				Classification according to ACMG standards
					Nucleotide	Amino acid					PolyPhen ‐2	SIFT	Human Splicing Finder	Mutation Taster
CDKL5	52	Heterozygous frameshift deletion	12	NM_003159.2	c.1849delC	p.Arg617Valfs*4	Upstream of three putative sites at C‐terminal	Not found	Novel	De novo	NA	NA	NA	+	Pathogenic
	73	Heterozygous frameshift deletion	7		c.427_430delATCA	p.Ile143Alafs*6	Catalytic domain	Not found	Novel	DNA of parents not available	NA	NA	NA	+	Likely pathogenic
KCNQ2	76	Heterozygous missense	7	NM_172107.3	c.944G>A	p.Gly315Glu	Calmodulin‐binding domain Helix A	Not found	Novel	De novo	+/1	+/0	NA	+	Likely pathogenic
	68	Heterozygous missense	6		c.850T>C	p.Tyr284His	Pore‐forming P‐loop	Not found	Novel	De novo	+/0.993	−/0.13	NA	+	Likely pathogenic
SCN8A	16	Heterozygous missense	27	NM_014101.3	c.4850G>A	p.Arg1617Gln	S4 of transmembrane domain IV	Not found	Reported22, 31, 32	De novo	+/1	+/0	NA	+	Pathogenic
DNM1	72	Heterozygous missense	4	NM_004408.3	c.431C>T	p.Pro144Leu	GTPase domain	Not found	Novel	Mother is not carrier; DNA of father not available	+/1	+/0	NA	+	Uncertain significance
PNPO	55	Compound heterozygous missense and frameshift deletion	5	NM_018129.3	c. 481C>G	p.Arg161Gly	Between helix 3 and 4	MAF= 0.0002313 for East Asian	Reported in ClinVar (Likely pathogenic)	Mother‐carrier of p.R161G; Father‐carrier of p.Pro150Argfs*27	+/1	+/0	NA	+	Likely pathogenic
					c.448_451delCCTG	p.Pro150Argfs*27	Between strand 5 and helix 3	Not found	Reported in ClinVar (Pathogenic/Likely pathogenic)		NA	NA	NA	+	Pathogenic
SLC9A6	7	Hemizygous splice site	Intron 6	NM_001042537.1	c.794‐2A>G	−	Transmembrane domain 7	Not found	Novel	Mother‐carrier	NA	NA	+	NA	Likely Pathogenic
	13	Hemizygous frameshift deletion and insertion (indels)	6		c.838_839delinsG	Leu280Alafs*17	Extracellular region between transmembrane domain 7 and 8	Not found	Novel	De novo	NA	NA	NA	+	Pathogenic
ALG13	75	Heterozygous missense	3	NM_001099922.2	c.320A>G	p.Asn107Ser	Conserved domain that may be important for catalytic activity	Not found	Reported15, 33, 34, 35, 36	De novo	−/0.437	+/0	NA	+	Pathogenic
TUBA8	1	Compound heterozygous missense	3	NM_018943.2	c.235C>T	p.Arg79Trp	No information available	MAF=0 for East Asian	Novel	Mother‐carrier of p.Arg79Trp; father‐carrier of p.Asn186Ser	+/1	+/0	NA	+	Uncertain significance
			4		c.557A>G	p.Asn186Ser		Not found			+/1	+/0	NA	+

^aAllele frequency from the ExAC database (http://exac.broadinstitute.org/).

^bFor Polyphen‐2, “+” indicates the variant is probably damaging and “−” indicates that it is benign. For SIFT analysis, “+” indicates the variant affects protein function and “−” indicates that it is tolerated. For Human Splicing Finder, “+” indicates the variant break the acceptor site and most probably affects splicing. For Mutation Taster, “+” indicats that it is disease causing.