Microdeletions in 9q33.3-q34.11 in five patients with intellectual disability, microcephaly, and seizures of incomplete penetrance: is STXBP1 not the only causative gene?

Ehret, Julia K.; Engels, Hartmut; Cremer, Kirsten; Becker, Jessica; Zimmermann, Johannes P.; Wohlleber, Eva; Grasshoff, Ute; Rossier, Eva; Bonin, Michael; Mangold, Elisabeth; Bevot, Andrea; Schön, Stefanie; Heilmann-Heimbach, Stefanie; Dennert, Nicola; Mathieu-Dramard, Michèle; Lacaze, Elodie; Plessis, Ghislaine; de Broca, Alain; Jedraszak, Guillaume; Röthlisberger, Benno; Miny, Peter; Filges, Isabel; Dufke, Andreas; Andrieux, Joris; Lee, Jennifer A.; Zink, Alexander M.

doi:10.1186/s13039-015-0178-8

Molecular Cytogenetics

Table 1 Main clinical findings in patients with microdeletions of 9q33.3-q34.1

From: Microdeletions in 9q33.3-q34.11 in five patients with intellectual disability, microcephaly, and seizures of incomplete penetrance: is STXBP1 not the only causative gene?

		Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Campbell et al. 2012 [11] (patient 3)	Campbell et al. 2012 [11] (patient 10)	Saitsu et al. 2008 [1] (patient 1)	Saitsu et al. 2012 [12] (Patient 2231^a)	Mignot et al. 2011 [13] (patient 3)
Deletion size		1.76 Mb	1.20 Mb	432 kb	4.13 Mb	1.23 Mb	2.65 Mb	830 kb	2.10 Mb	2.85 Mb	3.3 Mb
ISCN 2013		arr [hg19] 9q33.3q34.11 (129,463,613–131,224,189) × 1	arr [hg19] 9q33.3q34.11 (129,630,976–130,833,333) × 1	arr [hg19] 9q33.3 (129,688,382–130,120,163) × 1	arr [hg19] 9q33.3q34.11 (128,870,221–132,995,660) × 1	arr [hg19] 9q33.3q34.11 (129,950,179–131,180,179) × 1	arr [hg19] 9q33.3q34.11 (129,473,714–131,633,299) × 1	arr [hg19] 9q33.3q34.11 (129,843,508–130,681,956) × 1	arr [hg19] 9q33.3q34.11 (129,060,488–131,199,630) × 1	arr [hg19] 9q33.3q34.11 (129,980,488–132,830,579) × 1	n.r. del 9q33.3–q34.11
Affected genes		RALGPS1, ANGPTL2, GARNL3 + 48 RefSeq genes incl. STXBP1	RALGPS1, ANGPTL2, GARNL3 + 28 RefSeq genes incl. STXBP1	RALGPS1, ANGPTL2, GARNL3	RALGPS1, ANGPTL2, GARNL3 + 92 RefSeq genes incl. STXBP1	RALGPS1, GARNL3 + 45 RefSeq genes incl. STXBP1	RALGPS1, ANGPTL2, GARNL3 + 58 RefSeq genes incl. STXBP1	RALGPS1, ANGPTL2, GARNL3 + 22 RefSeq genes incl. STXBP1	RALGPS1, ANGPTL2, GARNL3 + 50 RefSeq genes incl. STXBP1	RALGPS1, GARNL3 + 86 RefSeq genes incl. STXBP1	RALGPS1, ANGPTL2, GARNL3 + > 9 RefSeq genes incl. STXBP1
Origin		De novo	De novo	Maternal	De novo	De novo	De novo	De novo	De novo	De novo	De novo
Age		3 y	5 y	6 y	5 y, 6 mo	11 y, 7 mo	6 y	6 y	2 y, 11 mo	1 y, 7 mo	10 y
Sex		Female	Male	Female	Female	Female	male	Male	Female	Male	Female
Birth parameters	Length	<10^th centile	<3^rd centile	25^th centile	10^th centile	ND	n.r.	n.r.	−2.3 SD	Normal	~10^th centile (est.)
	Weight	10^th centile	3^rd centile	50^th centile	10^th centile	0.4^th–2^nd centile	n.r.	n.r.	−2.4 SD	Normal	~10^th centile (est.)
	OFC	<3^rd centile	<3^rd centile	10^th centile	10^th centile	ND	n.r.	n.r.	−0.8 SD	Normal	ND
Growth parameters (at examination)	Height	10^th centile	4.5 cm < 3^rd centile	~6 cm < 3^rd centile	3^rd centile	0.4^th centile	n.r.	n.r.	<−2SD^a	n.r.	10^th centile
	Weight	25–50^th centile	10^th centile	10–25^th centile	10^th centile	25^th centile	n.r.	n.r.	<−2SD^a	n.r.	75–90^th centile
	OFC	~1.5 cm < 3^rd centile	2 cm < 3^rd centile	~0.5 cm < 3^rd centile	10^th centile	<0.4^th centile	n.r.	n.r.	40.0 cm (<< 3^rd centile)^a	−3SD	50–75^th centile
Microcephaly		+	+	+	–	+	+	n.r..	n.r.	+	+
Intellectual disability		+	+	+	+	+	+	+	+	+	+
Speech		Delayed (only syllables)	No speech	No speech (some syllables and cries)	No speech	Delayed (few words)	Severely impaired	Severely impaired	No speech	n.r.	Delayed (few words)
Walking		No (no crawling/sitting/standing)	Yes (only with assistance)	Yes (walking age 22 mo)	No	Yes (walking age 4 y)	n.r.	n.r.	No	n.r.	No
Seizures		–	–	+	+	–	+	–	+	+	+
EEG		Pathologic	Pathologic	Normal	Pathologic	Normal	Right temporal spikes	Normal	Suppression-burst pattern	Suppression-burst pattern	Disorganized background activity, multifocal spikes, spike and spike-wave bursts
Brain MRI		Mildly delayed myelination	Delayed myelination, unilateral temporal closed lip schizence-phaly	Bilateral temporo-occipital pachygyria with heterogenous “nodules” of grey	Normal	Normal	Chiari type I malformation	Normal	Cortical atrophy, diffuse hypomyeli-nation, thin corpus callosum, cerebellum and brain stem atrophy (at 12 mo)	Thin corpus callosum, relatively small cerebellum (2 mo)	Global atrophy of cerebral hemispheres
Muscular hypotonia		+	+	+	+	+	+	+	+	n.r.	n.r.
Dysmorphisms		Round face, high frontal hairline, telecanthus, upslanting palpebral fissures, short nose with depressed bridge, thin upper lip, low-set ears with attached lobules, short neck, tapering fingers with ridged nails, talipe equinus	Arched eyebrows, slightly upslanting palpebral fissures, smooth philtrum, widely-spaced teeth, thin upper lip	Short nose, anteverted nares, high frontal hairline, dimple chin, talus valgus bilateral	Arched eyebrows, telecanthus, horizontal palpebral fissures, flat nasal bridge, retrognathia, bilateral 5th finger clinodactyly, 1st fingers: absent nails, talipe equinus	Round face, round eyes, long eyelashes, short nose, thin upper lip, slightly everted lower lip, small hands and feet	Dysmorphic features	Mild dysmorphic features	n.r.	Midface hypoplasia^a	dysmorphic features
Ocular findings		Strabismus	Strabismus, hypermetropia	Strabismus	Strabismus, retinopathy of prematurity, bilateral microphtalmia	Strabismus	Strabismus	–	n.r.	n.r.	n.r.
Behavior		Bruxism	Cheerful mannerism	Autistic features, stereotypic hand movements	ND	Hyperactive, sleep difficulties	n.r.	n.r.	n.r.	n.r.	Stereotypies
Other findings		Recurrent otitis media, lack of pain sensation	Hypotonic-ataxic movement disorder	Recurrent otitis media, failure to thrive	Forearm malformation, non-ossified and dislocated patellae, nephropathy	Trunk and gait ataxia, pes planovalgus, celiac disease, overweight		Ataxia	Spastic quadriplegia	Cleft lip/palate, ventricular septal defect, overlapping fingers, small penis, spastic quadriplegia, multiple arthrogryposis	Absent thumbnails, nails of 2nd fingers hypoplastic

Summary of patient phenotypes and deletions
est. estimated, ND not determined, n.r. not reported, OFC occipitofrontal circumference, SD standard deviation, + present, – absent, y years, mo months
^aPersonal communication. Recurrent dysmorphisms and ocular findings are italicized

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