Table 1.

Male individuals with CASK mutations

Patient	CASK mutation	Birth OFC/W/L (SD)	Age	OFC a (SD)	Height a (SD)	Weight a (SD)	DD/ID	Tonus	Seizures EEG	Other neurologic anomalies	Eye findings	Sensorineural hearing loss	Other anomalies	Face	MRI	Overall phenotype
Pat 1	c.704_708del p.K236Efs*10 ex 7 dn	w 37 +3 -4.2/-3.2/?	† at 7 m	−5.9 (4.5 m)	−4.8 (6 m)	−1 (6 m)	profound, no development	severe hypotonia	intractable seizures	apnoeas, inability to swallow	optic atrophy	+	ASD, bil. clubfeet	dolichocephaly, puffy eyelids, broad nasal bridge, bulbous tip of nose, severe retromicrognathia, ear dysplasia, fleshy ear lobes	severe hypo CBL + pons + medulla, simplified gyri, cortical atrophy	MICPCH Severe epilepsy
Pat 2	Dup ex 10–16 dn	w 37 +3 -2.5/-1.9/-1.5	10 m † at 21 m	progressive microcephaly	−2.4	−2.8	profound	severe hypotonia	probably Ohtahara s., burst suppression		macropapilla, optic atrophy?	+?	long convex fingernails, overriding 2nd toes, linear blisters right leg, needed PEG	retrognathia, fleshy uplifted ear lobules	significant hypo CBL + pons	MICPCH Severe epilepsy
Pat 3	c.1A > G ex 1 dn	−1.3/-0.3/?	5 y	−5 (3 y)	−3	−2	profound, no development	severe hypotonia	intractable seizures		opticus hypoplasia	–	AVSD, tapering fingers, edema of the dorsum of hands and feet, needed PEG	long eyelashes, short nose, large ears with fleshy uplifted ear lobules	small brain, hypo CBL + pons	MICPCH Severe epilepsy
				−3.7 (5 y)
Pat 4	c.79C > T p.R27* ex 2 dn	w 33 +2 -2.57/-1.14/-1.73	15 m	−9.0	−3.0	−1.67	profound	severe hypotonia	intractable seizures, burst suppression	apnoea-bradycardy-syndrome, inability to swallow	optic atrophy?		VSD, short limbs, contractures of fingers	plagiocephaly, metopic ridge	severe hypo CBL + pons, progressive cortical atrophy, progressive hypomyelination	MICPCH Severe epilepsy
Pat 5	Dup ex 4–20 mos	w 36 +1 -1.8/0/0.3	7 m	−7.8 (9 m)	−2.1 (9 m)	−0.6 (9 m)	severe	hypertonia	spasms and myoclonic seizures, no hypsarrhythmia	–	hyperopia	?	micropenis, cryptorchidism	sparse hair, broad nasal bridge, epicanthal folds, long philtrum, retromicrognathia, fleshy uplifted ear lobules	small brain, hypo CBL + pons	MICPCH epilepsy
Pat 6	Del ex 1 mos	−2.9/-1.1/-1.7	16 m	−6 (11 m)	−2 (11 m)	−1.6 (11 m)	severe	hypertonia of limbs	–	–	hyperopia, strabism	–	cryptorchidism	broad nasal bridge, epicanthal folds, long philtrum, prominent premaxilla, mild retrognathia, simple/thin auricle	hypo CBL + pons	MICPCH
Pat 7	Del ex 3–9 mos	w 37–0.93/-0.5/-0.87	29 m	−3.56 (29 m) -2.55 (5;3 y)	−3.5 (29 m) -2.42 (5;3 y)	−1.97 (29 m) -1.45 (5;3 y)	severe	tonus regulation disorder	–	mild ataxia	–	–	–	prominent nasal bridge, thin upper lip, pointing chin	mild hypo CBL + pons mildly simplified gyri	MICPCH
Pat 8	Dup ex 1–5 mat	−2 /0/-1.4	20 m	−5	−2	−2	Mild to moderate DD		–	–			FTT	long flat philtrum	mildly smaller frontal lobes, small CC (frontal), CBL and otherwise normal	MIC + DD
Pat 16b	c.1061T > C p.L354Pc ex 12		5 y				profound, no development		West s., intractable seizures					large eyes, large ears, broad nasal bridge, broad nasal tip, epicanthal foldsd	MICPCH	MICPCH Severe epilepsy
Pat 1e	Del ex 2 matf	−1.2/-2/-1.4	4 y	−2.7 (1.4 y)			profound		Ohtahara s.				Long slender fingers, micropenis, needed tracheostomy + PEG	micrognathia, short neck	severe hypo CBL, hypo ponsd	MICPCH Severe epilepsy
Pat 2e	c.1A > G ex 1 dn	−2.7/-3.3/-2.8	4 y				severe	hypertonia of limbs	Ohtahara s.		PHPV	–	short upper arms, overlapping fingers, clinodactyly	micrognathia, high arched palate	severe CBL hypo, hypo ponsd	MICPCH Severe epilepsy
Case reportg	c.227_228del p.E76Vfs*6 ex 3 dn	0/0.1/1.4	8 m	−5.4			severe	hypotonia	early myoclonic encephalopathy (EME)	dystonia, chorea	optic atrophy		CP, tetralogy of Fallot, AMC, hydronephrosis, VUR, needed tracheostomy	micrognathia	severe hypo CBL + pons	MICPCH Severe epilepsy
Pat 13h	c.278 + 1G > A in 3 dn	−2/0/-0.5	16 m	−6	−2		profound	profound hypotonia	intractable seizures, spasms + tonic seizures, suppression-burst	spastic tetraparesis, dystonia	optic atrophy		long slender fingers with contractures, needed PEG	retrognathia, high arched palate, low-set ears with prominent lobules, down-slanted palpebral fissures, broad nasal bridge	very severe hypo CBL, hypo pons	MICPCH Severe epilepsy
Pat 12h	c.316C > T p.R106* ex 4 mos	−3/-1.5/-2	15 y	−3.5	−3.5		severe		–	dystonia, dyskinesia	–	–		well-arched eyebrows, broad nasal bridge, hypertelorism?, anteverted nares, full lipsd	mild hypo CBL	MICPCH
Pat 5i	c.915G > A p.(=) ex 9 dn		† at 2 w	microcephaly					?						severe hypo CBL + pons, thin and unmyelinated CC	MICPCH
Pat II 4j	Fam V c.2183A > G p.Y728C ex 23 (2 ♂)		14 y	−4.4k	−2.9	thin	severe				N, strabism, optic atrophy			synophris, high nasal bridge, upslanted palpebral fissures, short columellad	hypo CBL, pachygyria	MICPCH + N
Pat II 2j			19 y	−2.4k	−1.7	thin	moderate				N, astigmatism			similar to II 4	ND	MIC + Moderate ID + N
Pat IV 1j,l	Fam 74 c.2129A > G p.D710G ex 22 (4 ♂)		42 y	normal	normal		mild			hand tremor	N, strabism			no dysmorphism	ND	Mild ID + N
Pat III 3j,l				98th cen	normal	obese	mild			tremor, unsteady gait	N, strabism				ND	Mild ID + N
Pat III 12j,l				98th cen	normal	obese	mild				N				normal	Mild ID + N
Pat III 6j,l			59 y	normal	normal		mild							no dysmorphism	ND	Mild ID
Pat IV 1j,l	Fam 16 c.802T > C p.Y268H ex 8 (4 ♂, 1 without clinical description)			normal	normal		severe/profound		+	toe walker	no N		autistic	no dysmorphism	ND	Severe ID
Pat III 4j,l							severe		+		no N				ND	Severe ID
Pat II 3j,l							severe			toe walker	no N		obsessive behaviour		ND	Severe ID
three Patj,l	Fam 123 c.2756T > C p.W919R ex 27 (3 ♂)			normal	tall		mild		+, in one of three patients at age 17 y		N			no dysmorphism	ND	All 3: Mild ID + N
Pat III 1j,l	Fam 245 (K8919) c.1186C > T p.P396S ex 13 (4 ♂, 2 without clinical description)		58 y	0	short stature, 152 cm		profound			tremor, unsteady gait				flat mid face, open mouth, eversion of lower lip	ND	Severe IDS
Pat III 4j,l			52 y	0	short stature, 147 cm		severe				strabism			flat nasal bridge, anteverted nares, wide mouth, broad palate, broad grooved tongue, short broad neck	ND	Severe IDS
Pat III 3j	Fam 683 c.2521-2 A > T in 25 (4 ♂)		46 y	+1.6	−2.2		mild		+, absences	–	N, high myopia			no dysmorphism	ND	Mild ID + N
Pat II 3j							mild		+		N, strabism, myopia, astigmatism				ND	Mild ID + N
Pat II 4j							mild		–		N, high myopia, optic atrophy, retinal pigment anomalies				ND	Mild ID + N
Pat II 5j							mild		+		N				ND	Mild ID + N
Pat III 26m	c.83G > T p.R28L ex 2 (3 ♂)		2 y	relative macrocephaly	50-75th cen	25-50th cen	marked	hypotonia	EEG mildly abnormal		–	+	hyperactivity, aggressive behaviour, constipation	prominent forehead, frontal upsweep, hypertelorism, depressed nasal bridge, long philtrum, micrognathiad	normal (on CT)	IDS
Pat II 11m			34 y	relative macrocephaly			profound	hypotonia in infancy	+				aggressive behaviour, constipation	prominent forehead, hypertelorism, broad long philtrumd	ND	IDS
Pat II 17m			16 y		short stature		+, unspecified	hypotonia in infancy				+	hyperactivity, constipation, cryptorchidism	prominent forehead, frontal upsweep, long philtrum, epicanthal foldsd	ND	IDS

Legends: The eight first listed patients (Pat 1-8 in bold) are described in detail in the manuscript, patients listed below have been reported previously. +, present; −, absent; †, died; AMC, arthrogryposis multiplex congenita; ASD, atrial septal defect; AVSD, atrioventricular septal defect; bil., bilateral; CBL, cerebellum; CC, corpus callosum; cen, centile; CP, cleft palate; CT, computed tomography; DD, developmental delay; Del, deletion; dn, de novo; Dup, duplication; EEG, electroencephalogram; ex: exon; F, female; Fam, family; FTT, failure to thrive; hypo, hypoplasia; ID, intellectual disability; IDS, syndromic intellectual disability; in, intron; L, length; m, months; mat, maternally inherited; MIC, microcephaly; MICPCH, microcephaly with pontine and cerebellar hypoplasia; mos, somatic mosaicism; MRI, magnetic resonance imaging; N: nystagmus; ND, not documented; OD, right eye; OS, left eye; Pat, patient; PEG, percutane g-tube; PHPV, persistent hyperplastic primary vitreous; s., syndrome; SD, standard deviation; VSD, ventricular septal defect; VUR, vesicoureteral reflux; W, weight; w, week of gestation; y, year(s).

^aat last follow up (if not specified otherwise).

^bTakanashi et al., 2012 [5].

^cin original publication wrongly reported as p.L348P.

^dbased on figures/photographs shown in publication.

^eSaitsu et al., 2012 [9].

^fthe mother is a somatic mosaic for the CASK mutation.

^gJinnou et al., 2012 [18] and Nakamura et al., 2014 [8].

^hBurglen et al., 2012 [2].

ⁱNajm et al., 2008 [1].

^jHackett et al., 2010 [10].

^kin Table 1 of the original publication wrongly listed as normocephaly (absolute values were given in the text).

^lTarpey et al., 2009 [12].

^mPiluso et al., 2003 [19] and 2009 [11].