Report of a de novo c.2605C > T (p.Pro869Ser) change in the MED13L gene and review of the literature for MED13L-related intellectual disability

Yi, Zhi; Zhang, Ying; Song, Zhenfeng; Pan, Hong; Yang, Chengqing; Li, Fei; Xue, Jiao; Qu, Zhenghai

doi:10.1186/s13052-020-00847-y

Table 1 Clinical features of described patients with MED13L missense mutations and in silico-analysis results of these mutations

From: Report of a de novo c.2605C > T (p.Pro869Ser) change in the MED13L gene and review of the literature for MED13L-related intellectual disability

Literature		Our case	[2]			[15]	[16]	[17]	[18]	[14]	[19]	[13]
Mutations		c.2605C > T (Pro869Ser)	c.752A > G (Glu251Gly)	c.5615G > A (Arg1872His)	c.6068A > G (Asp2023Gly)	c.4247G > A (Arg1416His)	*c.2579A > G (Asp860Gly)*	c. 5371 A > T (Ser1791Cys)	c.5695G > A (Gly1899Arg)	*c.2579A > G (Asp860Gly)*	c.5282C > T (Prol1761Leu)	c.187 T > C (Cys63Arg)
Inheritance		De novo	maternally inherited	inheritance: NM	inheritance: NM	homozygous	De novo	Paternally inherited	De novo	De novo	NM	De novo
Exon		15	6	25	28	19	15	24	25	15	23	2
Domain			N-terminal domain	C-terminal domain	C-terminal domain	MID-MedPIWI	α-helical sequence		C-terminal domain	α-helical sequence	C-terminal domain	N-terminal domain
SIFT		damaging	damaging	tolerated	tolerated	damaging	tolerated	damaging	damaging	tolerated	tolerated	damaging
Polyphen2		probably damaging	possibly damaging	probably damaging	probably damaging	probably damaging	probably damaging	probably damaging	probably damaging	probably damaging	benign	probably damaging
Mutation taster		disease causing	disease causing	disease causing	disease causing	disease causing	disease causing	disease causing	disease causing	disease causing	polymorphism	disease causing
Mutation taster		disease causing	disease causing	disease causing	disease causing	disease causing	disease causing	disease causing	disease causing	disease causing	mRNA expression levels are significantly decreased revealed by qRT-PCR	disease causing
ID		+	Except dTGA, there are no other clinical features provided in these three patients			+	+	+	+	+	+	+
Speech impairment		+				NM	NM	+	+	+	+	+
Delayed milestones		+				NM	NM	NM	+	+	+	+
Growth parameter	weight	low				NM	NM	NM	low	NM	NM	NM
Growth parameter	height	short				NM	NM	NM	–	NM	NM	NM
Head deformities		microcephaly				NM	NM	NM	NM	NM	NM	NM
Behavioral difficulty/autism		+				NM	NM	+	Autism/auto-aggression	poor attention span	anxiety and disruptive and aggressive behavior	Self-harm, autism
Hypo- or hyper-tonia		Hypotonia				NM	NM	NM	Hypotonia	Hypotonia	Hypotonia/feeding difficulties	Hypotonia since birth whereas turn hypertonic since 4 y 10 m
Craniofacial deformity and other dysmorphic features		frontal bossing, low-set ears, hypertelorism, epicanthus, depressed nasal bridge, bulbous nasal tip, cupid-bow upper lip combined with open mouth appearance, micrognathia				NM	small dysplastic low-set ears, bulbous nasal tip, large mouth, single transverse palmar crease of the right hand	No dysmorphic features	asymmetric face, strabismus, left eye ptosis, ocular hypertelorism, downslanting palpebral fissures, bilateral epicanthus, wide, depressed nasal root, tented upper lip with frequent drooling, and low set ears	squared, low set ears with rather narrow ear lobes, mild ptosis, flat malar region, mild broadening of the nose, retrognathia	right-sided torticollis, asymmetric facies with simple uncurled slightly low-set right ear that protrudes from the head, enlargement or protrusion of the skull, and two small cafe au lait spots	reduced palpebral fissures, nasal base enlargement, enlarged plane philtrum, a thin upper lip, low-set ears, and a prominent columella
Cardiac anomalies		mild aortic coarctation, mild aortic regurgitation, slight tricuspid regurgitation	dTGA	dTGA	dTGA	NI	NM	NM	patent ductus arteriosus	NI	atrial septal defect	NI
Urinary system		Congenital UPJO combined with high ureter attachment of right				NM	NM	NM	NM	NI	NM	NM
Miscellaneous		Odontoprisis, appendicular muscular atrophy, hyperlaxity of the joints, scoliosis, spontaneous facture of femur							unilateral hearing loss, atopic dermatitis	With no muscle weakness, but was still clumsy, some hyperlaxity of the joints and skin
Epileptic seizure		No clinically observed seizures				NM	+	–	NM	+ intractable	atonic or absence seizures	NM
MRI abnormalities		enlarged bilateral lateral ventricles at 5 months old				NM	NM	NM	a prominence of subarachnoid space, predominantly frontal, ventriculomegaly and mega cisterna magna	mild dilatation of the lateral ventricles, a segmental thinning of the posterior part of the body of the corpus callosum	NM	Normal at 3 y 5 m
EEG abnormalities		spike and slow wave colligation and multi-spike and slow waves in bilateral occipital and posterior temporal region, as well as rapid rhythm distribution in the occipital area				NM	NM	NM	Normal	NM	NM	frequent epileptiform discharges during sleep in the left parietotemporal region and in the right centrotemporal region in absence of continuous spikes and waves during slow-wave sleep
Literature		[12]									[11]	Proportion (for the 18 patients who phenotypes are reported)
Literature		P14	P20	P21	P22	P23	P28	P32	P33	P35	[11]
Mutations		c.6485C > T (Thr2162Met)	c.2597C > T (Pro866Leu)	c.6488C > T (Ser2163Leu)	c.2930C > T (Ala977Val)	c.6488C > T (Ser2163Leu)	c.2605C > T (Pro869Ser)	c.6530C > A (Ser2177Tyr)	c.6005C > T (Ser2002Leu)	c.2605C > T (Pro869Ser)	c.3392G > A (Cys1131Tyr)
Inheritance		De novo	De novo	NM	De novo	De novo	De novo	De novo	De novo	De novo	De novo
Exon		30	15	30	16	30	15	31	27	15	17
Domain		C-terminal domain		C-terminal domain		C-terminal domain		C-terminal domain	C-terminal domain
SIFT		damaging	damaging	damaging	tolerated	damaging	damaging	damaging		damaging
Polyphen2		probably damaging	probably damaging	probably damaging	probably damaging	probably damaging	probably damaging	probably damaging	probably damaging	probably damaging	probably damaging
Mutation taster		disease causing	disease causing	disease causing	disease causing	disease causing	disease causing	disease causing	disease causing	disease causing	disease causing
ID		+	+(severe)	+ (severe)	+	+ (severe)	+	+	+	+	+	18/18 (100%)
Speech impairment		+	+	+	+	+	+	+	+	+	+	16/18 (88.9%)
Delayed milestones		+	+	+	+	+	+	+	+	+	+	15/18 (83.3%)
Growth parameter	weight	NM	NM	NM	NM	NM	NM	NM	NM	NM	low	3/18 (16.7%)
Growth parameter	height	NM	NM	NM	NM	NM	NM	NM	NM	NM	short	2/18 (11.1%)
Head deformities		NM	NM	NM	NM	NM	NM	NM	NM	NM	NM	1/18 (5.6%)
Behavioral difficulty/autism		–	Autistic features	Autistic features	Autistic features and behavioral troubles	–	NM	Autistic features and behavioral troubles	–	–	–	10/18 (55.6%)
Hypo- or hyper-tonia		–	Hypotonia	Hypotonia	–	Hypotonia	–	Hypotonia	Hypotonia	Hypotonia /Feeding difficulties	Severe Hypotonia/Feeding difficulties	12/18 (66.7%)
Craniofacial deformity and other dysmorphic features		hypotonic open-mouth, Thin vermillon border	Hypotonic open-mouth, Bulbous nasal tip	Hypotonic open-mouth, Bulbous nasal tip	–	Up-slanting palpebral fissures, Bulbous nasal tip, Cupid-bow upper lip, Hypotonic open-mouth, Thin vermillon border, Deep philtrum	Up-slanting palpebral fissures, Bulbous nasal tip, Cupid-bow upper lip, Hypotonic open-mouth, Thin vermillon border, Deep philtrum, clinodactyly	Bilateral club foot	Up-slanting palpebral fissures, Bulbous nasal tip, Thin vermillon border, ectopic anus, bilateral talipes, colo-bomatous micro-phtalmia	Up-slanting palpebral fissures, Bulbous nasal tip, Cupid-bow upper lip, Hypotonic open-mouth, Thin vermillon border, Deep philtrum	Displaced right pupil, bilateral microphthalmia, irido-corneal synechiae on the left, frontal bossing, short palpebral fissures, long eye lashes, broad straight eyebrows, depressed nasal bridge, Open mouth appearance, protrusion of the tongue	15/18 (83.3%)
Cardiac anomalies		NI	NI	NI	NI	NI	coarctation of the aorta	NI	patent foramen ovale	NI	NI	5/18 (27.8%)
Urinary system		Kidney cysts	NM	NM	NM	NM	double ureter	NM	NM	NM	NM	3/18 (16.7%)
Miscellaneous			Nystagmus, craniosynostosis, ataxia			Vertebral artery occlusion, ataxia	Intrauterine growth retardation	Ataxia	Intrauterine growth retardation	Hearing Impairment, myopia	Inguinal hernia in neonatal period, spastic paraparesis, dystonic movements of the extremities and the tongue,
Epileptic seizure		–	+	+	–	–	+	+	–	+	–	8/18 (44.4%)
MRI abnormalities		Normal	Normal	Normal	Focal cortical dysplasia	NM	Hypomyelination	NM	Ventriculo-Megaly	Diffuse cortical atrophy	a slightly enlarged ventricular system, partial agenesis of the corpus callosum, and a Dandy-Walker variant	8/12 (66.7%)
EEG abnormalities		NM	NM	NM	NM	NM	NM	NM	NM	NM	NM	2/18 (11.1%)

NM Not mentioned, NI Not involved, dTGA dextro-looped transposition of the great arteries

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