. 2023 May 9;14:1112153. doi: 10.3389/fgene.2023.1112153

TABLE 3.

The summary of clinical phenotype and diagnostic variants detected by ES in microcephaly cases.

ID	Patient ID	The clinical phenotype	Gene	Transcripts	Variant	Origin	Inheritance	ACMG classification	Zygosity	Associated condition	Function/pathway	Cerebral MRI finding	References for variants
1	P9445	moderate speech delay, cryptorchidism	KNL1	NM_144508.5	c.5184dup (p.Ile1729fs)	De novo	AD	P	Heterozygous	Microcephaly 4, primary, autosomal recessive (MIM: 604321)	Centrosome, spindle and microtubule organization	Enlargeme-nt in the left ventricle	Saadi et al. (2016)
2	P7900	VSD, hyperopia, astigmatism, Mild global DD	ANKRD11	NM_013 275.5	c.3223G>A (p. E1075K)	De novo	AD	P	Heterozygous	KBG syndrome (MIM: 148050)	Transcriptional regulation	No abnormality	_
3	A34241	Moderate global DD, Seizure, spastic hemiparesis	HDAC8	NM_018486.3	c.490C>T (p. Arg164Ter)	De novo	XLD	P	Heterozygous	Cornelia de Lange syndrome 5(MIM: 300882)	transcriptional regulation	Arachnoidal cyst	Kaiser et al. (2014)
4	P9483	Pulmonary atresia, patent ductus arteriosus, mild feeding difficulties	MYO18B	NM_032608.7	c.4087C>T (p. Arg1363Ter)	Maternal inherited	AR	LP	heterozygous	Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism (MIM: 616549)	neuronal proliferation and migration	Abnormal gyrus, corpus callosum dysgenesis, everted hippocampi	Alazami et al. (2015)
4	P9483		MYO18B	NM_032608.7	c.3639G>A (p. Gly1213 = )	Paternal inherited	AR	VUS	heterozygous		neuronal proliferation and migration		Alazami et al. (2015)
5	P9125	Blind, Retinal detachment, moderate global DD, vesicoureteral reflux	TUBGCP6	NM_020461.3	c.2066–6A>G	Maternal inherited	AR	LP	Heterozygous	Microcephaly and chorioretinopathy, autosomal recessive, 1 (MIM:251270)	transcriptional regulation	No abnormality	-
5	P9125		TUBGCP6	NM_020461.3	c.4485–31_4485-22delGCCCGCCCTG	Paternal inherited	AR	VUS	Heterozygous	-	-	-	-
6	A33033	Severe global DD, decreased reflexes, severe failure to thrive, congenital cataract, hepatomegaly	OSGEP	NM_017807.4	c.974G>A (p. Arg325Gln)	Paternal inherited	AR	LP	Heterozygous	Galloway-Mowat syndrome (MIM: 617729)	cell cycle regulation	Hypoplasia of cerebellar vermis	Chen et al. (2007)
6	A33033		OSGEP	NM_017807.4	c.740G>A (p. Arg247Gln)	Maternal inherited	AR	VUS	Heterozygous	Galloway-Mowat syndrome (MIM: 617729)	cell cycle regulation	Hypoplasia of cerebellar vermis	Chen et al. (2007)
7	A32966	Mild global DD, mild ID, hypotonia, failure to thrive, short stature, mild truncal adiposity	SLC26A4	NM_000441.2	c.1174A>T (p. Asn392Tyr)	Maternal inherited	AR	P	Heterozygous	Deafness, autosomal recessive 4, with enlarged vestibular aqueduct (MIM:600791)/Pendred syndrome (MIM: 274600)	Regulation of apoptosis and division	Cerebellar hypoplasia	_
7	A32966		SLC26A4	NM_000441.2	c.919–2A>G	Paternal inherited	AR	P	Heterozygous		Regulation of apoptosis and division	Cerebellar hypoplasia	_
8	A32860	Moderate speech delay, Mild global DD, EEG abnormalities, growth deficiency	SKIV2L	NM_006929.4	c.1120C>T (p. Arg374Ter)	Maternal + Paternal inherited	AR	P	homozygous	Trichohepatoenteric syndrome 2 (MIM:614602)	Centrosome, spindle and microtubule organization	No abnormality	_
9	A32741	Moderate global DD, severe progressive optic atrophy, moderate hyperopia, bilateral hearing loss	COL1A2	NM_000089.3	c.1072G>A (p. Gly358Ser)	De novo	AD	P	Heterozygous	Ehlers-Danlos syndrome, arthrochalasia type, 2(MIM:617821)	spindle and microtubule organization	Agenesis of corpus callosum	_
10	P9424	Distal spasticity, neurogenic clubfeet, growth deficiency, hemivertebra	EBP	NM_006579.2	c.328C>T (p. Arg110Ter)	De novo	XLD	P	Heterozygous	MEND syndrome (MIM:300960)	Stability of centriole	hypoplasia of the corpus callosum	_
11	A32706	Mild global DD, generalized hypotonia, VSD, torticollis	DOCK6	NM_020812.3	c.807-1G>A	Paternal inherited	AR	LP	Heterozygous	Adams-Oliver syndrome 2 (MIM:614219)	spindle and microtubule organization	cortical malformations	_
11	A32706	Mild global DD, generalized hypotonia, VSD, torticollis	DOCK6	NM_020812.3	c.377 + 5G>A	Maternal inherited	AR	VUS	Heterozygous	Adams-Oliver syndrome 2 (MIM:614219)	spindle and microtubule organization	cortical malformations	_
12	A32409	Moderate global DD, 2 episodes of seizure, inappropriate laughter, PA, muscular hypotonia	ZEB2	NM_014795.3	c.436G>T (p. Glu146Ter)	De novo	AD	P	heterozygous	Mowat-Wilsonsyndrome (MIM:235730)	Transcriptional inhibitor	The development or hypoplasia of the corpus callosum	Wakamatsu et al. (2001)
13	A32706	Mild–moderate motor DD, VSD, mild speech delay, short stature, behavior abnormalities, recurrent infections	TRIO	NM_007118.3	c.5302C>T (p. Arg1768Trp)	De novo	AD	LP	heterozygous	Intellectual developmental disorder, autosomal dominant 44, with microcephaly (MIM:617061)	cell cycle regulation	No abnormality	Mercer et al. (2008)
14	A31618	Moderate–severe global DD, pulmonary stenosis, muscular hypotonia, VSD	NIPBL	NM_133433.3	c.6983C>A (p. Thr2328Lys)	De novo	AD	P	heterozygous	Cornelia de Lange syndrome 1 (MIM:122470)	cell cycle regulation	No abnormality	Braddock et al. (1993)
15	A31843	Moderate–severe global DD, moderate–severe ID, VSD, Hemivertebra, duplication of kidney and hydronephrosis	FANCI	NM_001113378.1	c.3042C>G (p. Cys1014Trp)	Paternal inherited	AR	P	homozygous	Fanconi anemia, complementation group IMIM: 609053)	spindle	Megagyrus, widened lateral ventricle	Savage et al. (2015)
16	A31314	Severe global DD, severe ID, intermittent hyperventilation, distal hypertonia, short stature	PDHA1	NM_000284.3	c.1142_1145dupATCA (p. Trp383SerfsTer6)	De novo	XLD	P	Heterozygous	Pyruvate dehydrogenase E1-alpha deficiency (MIM:312170)	cell cycle regulation	schizencephaly	_
17	A31627	Severe global DD, sterotypic movements, tonus dysregulation, feeding difficulties	NIPBL	NM_133433.3	c.6983C>A (p. Thr2328Lys)	De novo	AD	LP	Heterozygous	Cornelia de Lange syndrome 1 (MIM:122470)	cell cycle regulation	Enlargeme-nt in the left ventricle	Braddock et al. (1993)
18	P9017	DD, VSD, muscular hypotonia	CLCN5	NM_001127898.3	c.934-1G>T	Maternal inherited	XLR	LP	hemizygous	Hypophosphatemic rickets (MIM:300554)	chromosome condensation, cell cycle regulation	Atrophy of the white matter	_
19	A34124	Learning disability, myopia, short stature, ADHD, short stature	13q14.2-q32.1	chr13:49833482–96743823: 46.9 Mb deletion		De novo	-	P	-	-	-	-	-
20	A33056	Fine motor problems, VSD, moderate–severe speech delay, PA	NIPBL	NM_133433	complete gene deletion	-		P	-	Cornelia de Lange syndrome 1 (MIM:122470)	cell cycle regulation	expansion of the lateral ventricle	-
21	P7789	Severe global DD, pain insensitivity, inappropriate laughter, cyanotic seizures	UBE3A	NM_000462	c.2576_2577delAA (p. K859RfsX24)	De novo	AD	P	Heterozygous	Angelman syndrome (MIM:105830)	Transcription	Macrogyria	_
22	A33126	Severe global DD, hypotonia, seizures, mild speech delay	CASK	NM_003688.3	c.1889_1895delTCATCCC (p. Leu630ProfsTer51)	De novo	XLD	P	Heterozygous	Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MIM:300749)	cell cycle regulation	Hypomyelination, thin corpus callosum	Moog et al. (2011)
23	P3376	Moderate global DD, VSD, recurrent subfebrile temperature, short stature, joint laxity	PHC1	NM_004426.3	c.100C>T (p. Arg34Ter)	De novo	AR	P	Heterozygous	Microcephaly 11, primary, autosomal recessive (MIM: 615414)	cell cycle regulation	Mild cortical atrophy	Awad et al. (2013)
23	P3376		PHC1	NM_004426.3	c.2041 + 3_2041+6delGAGT	Maternal inherited	AR	VUS	Heterozygous	Microcephaly 11, primary, autosomal recessive (MIM: 615414)	cell cycle regulation	Mild cortical atrophy	Awad et al. (2013)
24	A33057	Mild–moderate DD, strabismus, short stature, joint laxity, vesicoureteral reflux due to renal tubular ectasia, VSD, chronic obstipation, muscular hypotonia	TUBB2A	NM_001069.2	c.1162A>G (p. Met388Val)	De novo	AD	LP	Heterozygous	Cortical dysplasia, complex, with other brain malformations 5(MIM:615763)	microtubule organization	Hypoplasia of cerebellar vermis, thin corpus callosum	Cushion et al. (2014)
25	A35607	Mild–moderate motor DD, short stature	7q11.23	1.44 Mb deletion		De novo	_	_	_	Williams-Beuren syndrome (MIM:194050)	_	_	_
26	A33021	Mild–moderate global DD, cyanotic seizures, tonus dysregulation, short stature	WDR62	NM_001083961.1	c.321dupT (p. Asn108Ter)	Paternal inherited	AR	LP	homozygous	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations (MIM: 604317)	neuronal proliferation and migration	callosum dysgenesis, everted hippocampi	Darvish et al. (2010)
27	A35078	Fine motor problems, moderate ID, dysmetria, moderate–severe speech delay, VSD, short stature	PEX1	NM_000466.3	c.2966T>C (p. Ile989Thr)	Paternal inherited	AR	LP	Heterozygous	Peroxisome biogenesis disorder 1A (Zellweger) (MIM: 214100)	Transcription	Absence of corpus callosum	_
27	A35078		PEX1	NM_000466.3	c.1285G>A (p. Val429Ile)	Maternal inherited	AR	VUS	Heterozygous	Peroxisome biogenesis disorder 1A (Zellweger) (MIM: 214100)	Transcription	Absence of corpus callosum	_
28	A34098	Moderate global DD, PA, short stature	LAGE3	NM_006014.5	c.184A>G (p. Ile62Val)	Maternal inherited	XLR	LP	hemizygous	Galloway-Mowat syndrome 2, X-linked (MIM: 301006)	transcription	Macrogyria	Braun et al. (2017)
29	A31066	Moderate global DD, short stature	17p13.3	3.51 Mb deletion		De novo	_	_	_	Miller-Dieker lissencephaly syndrome (MIM:247200)	_	_	Schinzel et al. (1988)
30	A32068	Fine motor problems, Mild speech delay, short stature, right plagiocephaly	FANCI	NM_001113378.1	c.3187–2A>G	De novo	AR	LP	heterozygous	Fanconi anemia, complementation group I (MIM: 609053)	spindle	Enlarged subarachnoidal space	Savage et al. (2015)
30	A32068		FANCI	NM_001113378.1	c.3015G>C (p. Gln1005His)	Paternal inherited	AR	VUS	heterozygous	Fanconi anemia, complementation group I (MIM: 609053)	spindle	Enlarged subarachnoidal space	Savage et al. (2015)
31	P9989	Moderate–severe global DD, moderate ID, Dysmetria, short stature, bilateral cryptorchidism	PPFIBP1	NM_003622.4	c.403C>T (p. Arg135Ter)	De novo	AR	P	homozygous	Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities (MIM:620024)	Cell cycle regulation	dysplasia of the corpus callosum	Rosenhahn et al., 2015

XLR, X-linked recessive; P, pathogenic; AD, autosomal dominant; LP, likely pathogenic; AR, autosomal recessive; VUS, variants of unknown significance; XLD, X-linked dominant.

ADHD, attention deficit–hyperactivity disorder; DD, developmental delay; EEG, electroencephalogram; ID, intellectual disability; VSD, ventricular septal defect; PA, pulmonary atresia.