Genome Sequencing of Idiopathic Speech Delay

Table 2

Rare likely deleterious missense variants in intolerant genes identified in 13 singleton cases with speech delay.

Proband	Chr	Base (GRCh37)	Base (GRCh38)	Gene	Transcript	cDNA change	Protein change	gnomAD MAF	MIS_Z	pLI	Local missense intolerance	SIFT	PolyPhen	REVEL	GERP	Phenotype previously associated with heterozygous variants	Classification
01	1	53742664	53276992	LRP8	NM_001018054	c.G583A	p.G195S		2.77	1.00	Highly intolerant	D	P	0.669	2.91	—	VUS
02	1	10318654	10258596	KIF1B	NM_015074	c.A287G	p.Y96C		3.6	1.0	Intolerant	D	D	0.95	5.7	Charcot-Marie-Tooth neuropathy	VUS
03	4	140282956	139361802	NAA15	NM_057175	c.G1618T	p.D540Y		3.8	1.0	Intolerant	D	D	0.54	6.0	Intellectual disability, delayed speech and motor milestones, and autism spectrum disorder [53, 54]	VUS
04	2	54845255	54618118	SPTBN1	NM_003128	c.G688A	p.A230T	0	4.5	1.0	Intolerant	D	D	0.86	5.6	Intellectual disability, delayed speech, autistic features, and seizures [50, 51]	Likely pathogenic
	6	165863831	165450343	PDE10A	NM_001130690	c.A245C	p.Q82P	0	3.8	1.0	Intolerant	D	D	0.53	4.6	Striatal degeneration [61]	VUS
05	7	103124179	103483732	RELN	NM_005045	c.G10102A	p.G3368R		1.14	1.00	Intolerant	D	D	0.703	5.72	Autism [62], epilepsy [63], neurodevelopmental disorders [64], lissencephaly [65]	VUS/likely benign
	10	27405184	27116255	YME1L1	NM_001253866	c.G1711A	p.E571K	0	2.06	0.99	Intolerant	D	D	0.943	5.43	—	VUS
	12	49333815	48940032	ARF3	NM_001659	c.G224C	p.R75P	0	3.01	0.62	Highly intolerant	D	D	0.881	3.83	Neurodevelopmental disorder with brain and skeletal abnormalities [52]	Likely pathogenic
	14	35240770	34771564	BAZ1A	NM_182648	c.C3152T	p.A1051V		2.69	1.00	Intolerant	T	D	0.636	5.66	—	VUS
06	19	42777266	42273114	CIC	NM_001304815	c.G1331T	p.C444F	0	1.53	1.00	NA	NA	NA	NA	4.7	Intellectual disability, autism spectrum disorder, and ADHD [60]	VUS
07	9	140069703	137175251	ANAPC2	NM_013366	c.G2242A	p.E748K		2.43	1.00	Intolerant	D	D	0.506	4.32	—	VUS
	19	41183304	40677399	NUMBL	NM_001289979	c.T440C	p.V147A	0	3.18	1.00	Intolerant	D	D	0.596	5.31	—	VUS
08	5	45695972	45695870	HCN1	NM_021072	c.223_224ins; GCGGCGGCG	p.G74_E75; insGGG		3.72	1.0	Intolerant	NA	NA	NA	NA	Infantile epileptic encephalopathy [66]	Likely benign
	12	122626291	122141744	MLXIP	NM_014938	c.C2692G	p.P898A	0	1.87	0.98	Intolerant	D	D	0.72	5.5	—	VUS
09	9	130422360	127660081	STXBP1	NM_001032221	c.C298T	p.R100W		4.3	1.0	Intolerant	D	D	0.70	4.6	STXBP1-related disorders including neurodevelopmental delay and seizures [67]	Likely pathogenic/VUS
	10	75557014	73797256	ZSWIM8	NM_001242487	c.3403_3405del	p.K1137del		5.53	1.00	Intolerant	NA	NA	NA	NA	—	VUS
10	11	120312519	120441810	ARHGEF12	NM_001198665	c.C1139A	p.A380E	0	3.3	1.0	Highly intolerant	D	D	0.82	5.5	—	VUS
	20	50307357	51690818	ATP9A	NM_006045	c.A644G	p.D215G		4.2	1.0	Intolerant	D	D	0.79	5.3	—	VUS

Rare, likely deleterious missense variants located in brain-expressed transcripts intolerant to missense variation are listed. Chr: chromosome; MAF: minor allele frequency; MIS_Z: -score for missense constraint; pLI: probability of being loss-of-function intolerant; SIFT: Sorting Intolerant From Tolerant; PolyPhen: Polymorphism Phenotyping; REVEL: rare exome variant ensemble learner; GERP: Genomic Evolutionary Rate Profiling; NA: not available/not applicable; T: tolerated/benign; P: possibly damaging; D: deleterious; VUS: variant of unknown significance. Classification from ClinVar [44].