Utility of trio-based exome sequencing in the elucidation of the genetic basis of isolated syndromic intellectual disability: illustrative cases

Figures & data

Table 1 Main clinical findings of the patients in the cohort

Patients	Sex	Age (years)	Clinical signs
1	Male	5	Intrauterine growth restriction, premature birth, intellectual disability, autistic behavior, cardiac abnormalities (interatrial communication and pulmonary stenosis), cryptorchidism, facial dysmorphisms
2	Female	11	Intellectual disability, absent speech, seizures, bilateral congenital cataract, hypotonia of upper and lower limbs
3	Female	6	Intellectual disability, hypotonia, high-arched palate, facial dysmorphisms, renal and cardiac malformations
4	Male	11	Intellectual disability, absent speech, no ambulation, epileptic encephalopathy
5	Female	5	Intellectual disability, short stature, microcephaly, palpebral ptosis, myopia, decreased visual acuity, optic atrophy, neutropenia
6	Female	23	Intellectual disability, absent speech, bilateral hearing loss, facial dysmorphisms, arachnoid cyst, bilateral preauricular appendages, polycystic kidney disease
7	Male	17	Intellectual disability, short stature, and myotonia
8	Female	6	Intellectual disability, poor speech, facial dysmorphisms

Figure 1 Example of pathogenic mutations identified in the cohort.

Notes: (A) Image of the binary alignment map files showing the forward and reverse reads of a segment of the GABBR2 gene; the mutation from C to T in heterozygosity in the proband, not present in his parents, can be seen in dark blue. Underneath, Sanger sequencing validation of the C/T substitution, (B) Image of the BAM files showing the forward and reverse reads of a segment of the MID1 gene; the mutated allele, in heterozygosity in the mother and hemizygosity in the proband, is seen in dark blue. Underneath, Sanger sequencing validation of the C/T substitution.

Table 2 The candidate mutations identified in five of the patients of the cohort

Patients	Gene	Variation (ref/Alt)	Position	Exon	Inheritance pattern	Family segregation	Amino acid exchange	OMIM phenotype	Effect	Gnomad	dbSNP	ClinVar
1	RYR2	G/A	1:237957254	95	Dominant	Heterozygous, de novo	p.Asp4624Asn	600996, 604772	Missense	–	–	–
	MID1	C/T	X:10535359	2	X-linked	Inherited from the mother, hemizygous	p.Val77Ile	300000	Missense	0.0001	rs143416243	–
	ADAMTSL2	G/A	9:136419629	10	Recessive	Homozygous, inherited from heterozygous parents	p.Val364Ile	231050	Missense	–	rs35767802	–
4	GABBR2	C/T	9:101133817	12	Dominant	Heterozygous, de novo	p.Ala567Thr	–	Missense	–	–	–
5	NALCN	C/T	13:101717778	40	Recessive	Heterozygous, inherited from the father	p.Val1528Ile	615419	Missense	0.0122	rs767980482	–
	NALCN	C/A	13:101721179	38	Recessive	Heterozygous, inherited from the mother	p.Val1400Phe	615419	Missense	0.0186	rs771656968	–
	VPS13B	C/T	8:100654570	34	Recessive	Heterozygous, inherited from the father	p.Arg1943*	216550	LoF (stop gain)	0.0323	rs386834099	Pathogenic/likely pathogenic RCV000050092
	VPS13B	C/G	8:100865871	56	Recessive	Heterozygous, inherited from the mother	p.Tyr3443*	216550	LoF (stop gain)	–	–	–
6	DDX3X	T/C	X:41206163	15	X-linked	Heterozygous, de novo	p.Leu556Ser	300958	Missense	–	–	Likely pathogenic RCV000424111
8	CDK13	G/C	7:40087439	7	Dominant	Heterozygous, de novo	p.Asp855His	–	Missense	–	–	–

Note: Variants in bold are considered to be causative of the phenotypes.

Abbreviations: Alt, alternate nucleotide; LoF, loss of function; OMIM, Online Mendelian Inheritance in Man; Ref, reference nucleotide.