Whole-Exome Sequencing for Identifying Genetic Causes of Intellectual Developmental Disorders

Figures & data

Figure 1 Facial and limb features of the patient.

Table 1 The Clinical Features of 21 Patients with Intellectual Developmental Disorders

Proband	Mutant Genes	Visiting Age	Clinical Phenotype	Intellectual Developmental Disorder	History of Birth	MRI
1, M	RAB39B	11 m	IDD	Mild	Normal	Normal
2, M	ATRX	22 m	IDD, EP	Mild	Premature	Normal
3, M	CLCN4	36 m	IDD, EP	Mild	Normal	Ventriculomegaly
4, M	HCFC1	41 m	IDD	Moderate	Normal	Pachygyria
5, M	HCFC1	34 m	IDD, EP	Moderate	Normal	Normal
6, M	DYRK1A	8 m	IDD, EP	Mild	Normal	Ventriculomegaly
7, F	CASK	56 m	IDD, Rett syndrome	Severe	Normal	Normal
8, F	MECP2	68 m	IDD, ASD	Moderate	Normal	Normal
9, F	MECP2	67m	IDD, ASD, EP	Moderate	Normal	Normal
10, M	MECP2	6 y9m	IDD, EP	Moderate	Normal	Normal
11, M	CREBBP	29m	IDD	Severe	Premature, Intrauterine distress	Dilated bilateral lateral ventricle and third ventricle
12, M	None	20m	IDD	Severe	Intrauterine distress	Dilated external cerebral space
13, M	None	70m	IDD	Profound	Normal	Abnormal signals from the left lateral ventricle
14, M	None	70m	IDD	Severe	Normal	Agenesis of corpus callosum
15, M	None	8m	IDD, EP	Mild	Normal	Normal
16, M	None	21m	IDD	Moderate	Normal	Normal
17, M	None	11m	IDD	Moderate	Normal	Normal
18, M	None	8m	IDD, EP	Moderate	Normal	Normal
19, M	None	13 y	IDD	Moderate	Normal	Normal
20, M	None	13 y	IDD, ASD	Moderate	Normal	Abnormal signal in the right frontal area
21, M	None	2y2m	IDD	Moderate	Normal	Normal

Notes: IDD degree: mild (55≤DQ≤75; 50≤IQ≤69); moderate (40≤DQ≤54; 35≤IQ≤49); severe (25≤DQ≤39; 20≤IQ≤34); profound (DQ<25; IQ<20).

Abbreviations: IDD, intellectual developmental disorder; EP, epilepsy; ASD, autism spectrum disorders; y, years; m, months; M, male; F, female.

Table 2 The Gene Variants in 11 Children with Intellectual Developmental Disorders

Proband	Mutant Genes	Transcript	Varian Type	Nucleotide Changes	Amino Acid Changes	Position		Father	Mother	ACMG	Previous Report
1	RAB39B	NM_171998	Deletion mutation	c. 258–260delTCT	L88del	–	De novo	–	–	Pathogenic	No
2	ATRX	NM_000489	Missense mutation	c.4858A>C	S1620R	Exon18	Hemizygote	–	+	Likely pathogenic	No
3	CLCN4	NM_001830	Missense mutation	c.823G>A	V275M	Exon8	Hemizygote	N	N	Likely pathogenic	Yes
4	HCFC1	NM_005334	Missense mutation	c.4442C>T	T1481M	Exon18	Hemizygote	–	+	Likely pathogenic	No
5	HCFC1	NM_005334	Missense mutation	c.3845C>T	S1282L	Exon17	Hemizygote	–	+	Pathogenic	No
6	DYRK1A	NM_001396	Nonsense mutation	c.787 C >T	R263X,501	Exon6	De novo	–	–	Pathogenic	Yes
7	CASK	NM_003688	Splicing site mutation	c.1155+1G>A	–	IVS12	De novo	–	–	Pathogenic	No
8	MECP2	NM_004992	Nonsense mutation	c.763C>T	R255X,232	Exon4	De novo	–	–	Pathogenic	Yes
9	MECP2	NM_004992	Missense mutation	c.674C>G	P225R	Exon4	De novo	–	–	Pathogenic	Yes
10	MECP2	NM_001110792.1	Repeat mutation	c.18_23dupCGCCGC	A7_A8dup	–	Hemizygote	–	– or mosaicism	Uncertain significance	No
11	CREBBP	NM_004380	Frameshift mutations	c.3380delA	D1127AfsTer3	Exon18	De novo	–	–	Pathogenic	No

Figure 2 (Left): Chromatogram from Sanger sequencing of the CREBBP variant in the family. (Right): The protein tertiary structure of normal CREBBP protein (A) and mutant CREBBP protein (B) according the SWISS-MODEL analysis.

Table 3 Global Analysis of the Gesell Results

	Group	N	Average	SD	SE
Gross motor	Gene-Positive	10	51.5200	13.96319	4.41555
	Gene-negative	7	40.7143	14.47658	5.47163
Fine motor	Gene-Positive	10	47.7600	14.25476	4.50775
	Gene-negative	7	37.7143	17.85790	6.74965
Adaptability	Gene-Positive	10	48.1400	11.84232	3.74487
	Gene-negative	7	32.2857	20.58085	7.77883
Language	Gene-Positive	10	44.4000	17.60808	5.56816
	Gene-negative	7	37.2857	18.24568	6.89622
Social Competence	Gene-Positive	10	47.1700	13.34417	4.21980
	Gene-negative	7	42.0000	18.23001	6.89030

Table 4 Comparison of Gesell Results Between Gene Positive and Negative Group

		Levene Test
		F	P	95% CI
				Lower Limit	Higher Limit
Gross motor	Using Equivalent variance	0.211	0.653	−4.07913	25.69056
	Not using Equivalent variance			−4.41387	26.02530
Fine motor	Using Equivalent variance	0.410	0.532	−6.54515	26.63658
	Not using Equivalent variance			−7.80348	27.89491
Adaptability	Using Equivalent variance	2.302	0.150	−.87209	32.58066
	Not using Equivalent variance			−3.74745	35.45602
Language	Using Equivalent variance	0.024	0.879	−11.65182	25.88039
	Not using Equivalent variance			−12.07116	26.29973
Social Competence	Using Equivalent variance	3.243	0.092	−11.09489	21.43489
	Not using Equivalent variance			−12.74571	23.08571