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Table 1 Clinical features of four patients with de novo mutations in the last exon of the ZNF148 gene

From: Truncating de novo mutations in the Krüppel-type zinc-finger gene ZNF148 in patients with corpus callosum defects, developmental delay, short stature, and dysmorphisms

 

Patient 1

Patient 2

Patient 3

Patient 4

Gender and current age

Girl, 6.7 years

Boy, died on postnatal day 6 after sudden bradycardia

Girl, 11.7 years

Girl, 7 years

ZNF148 mutation

c.1792A > T; p.Lys598*

c.1583dup; p.Ser529Glufs*2

c.970dup; p.Ser324Phefs*14

c.1581_1582insC; p.Lys528Glnfs*3

Additional variants

SART3 c.1526A > G; p.Asn509Ser

TCERG1 c.2359G > A; p.Asp787Asn

None

PDCD4 c.1198C > G; p.Gln400Glu homozygous

COL3A1 c.3938A > G; p.K1313R; heterozygous, maternally inherited, MAF 0.26%; classified as VUS in ClinVar (RCV000181114.1)

Pregnancy

Uncomplicated, mother noted diminished fetal movements

Decelerative CTG just before birth

Uncomplicated

Renal cysts and heart defect on fetal ultrasound

Birth

Uneventful, 35 + 4 weeks

CS at 31 + 2 weeks, Apgar scores 2-4-7, not breathing, pale, hypotonic, and lactic acidosis postpartum

CS at 38 + 5 weeks, Apgar scores 5-6-8, hypotonic and hyporeactive, Continuous Positive Airway Pressure for respiratory insufficiency

Induced vaginal delivery at 36 + 0 weeks. Apgar scores 4-7-8. Apneic at delivery, responding to PPV. Started on PGE for known COA.

Birth weight

2.68 kg (–0.30 SD)

1.84 kg (+0.04 SD)

3.315 kg (+0.14 SD)

1.990 kg (–1.49 SD)

Birth length

47 cm (–0.37 SD)

39 cm (–2.62 SD)

49 cm (–0.50 SD)

42 cm (–2.55 SD)

Birth head circumference

32 cm (–0.75 SD)

29.2 cm (–0.37 SD)

35 cm (+0.49 SD)

28.5 cm (–3.2 SD)

Feeding problems

Severe, tube feeding need for sufficient caloric intake

Not applicable

Feeding problems during first week with 5 days of tube feeding

Feeding problems during neonatal period with tube feedings. Persistent FTT

Length

110.2 (–2.29 SD) at 6.6 years

40 cm (–2.5 SD) at 6 days

151.7 (+0.04 SD) at 11.3 years, catch up with growth hormone substitution therapy started at 3 years because of growth retardation (–2.48 at 2.7 years), and growth hormone deficiency

93.47 cm (–5.11 SD) at 6 years of age

Weight

17 kg (–1.09 SD for length) at 6.6 years

1.84 kg (+0.04 SD) at 6 days

38.4 kg (–0.33 SD for length) at 11.3 years

11.79 kg (0%ile, z-score –5.71) at 6 years of age

Head circumference

(–2.76 SD) at 6.5 years

29.2 cm (–0.37 SD) at 6 days

58.2 cm (+2.84 SD) at 11.3 years and fluctuating above and below +3 SD between 6 and 10 years

41 cm (–8.7 SD) at 6 years

Developmental milestones

Walked independently at 3 years. Spoke 3 years

Not applicable

Walked independently at 4 years and started talking > 3 years

Rolled over at 3 months. Crawled at 18 months. Walked independently at 4 years. Approximately 20 words

Cognition

WPPS1–III (2.6–3.1 years) at 3.7 years: TIQ 57 (95% CI 52–74) disharmonic profile: VIQ 72, PIQ 55.

WPPSI-III-NL 2.6–7.11 years) TIQ 59 (95% CI 54–71), VIQ 72 (68–85), PIQ 63 (57–77)

Mild intellectual delay

Not applicable

WISCIII at 8 years

Total IQ 58, verbal IQ 62, perfomal IQ 69 Attends school for children with severe learning problems

No formal developmental assessment. Attends elementary school receiving special education through the public school system. Uses communication devices for expressive language. Receptive language seems good

Head

Triangular-shaped face with pointed chin

Coarse face, slight frontal bossing

Slight frontal bossing, triangular-shaped face with pointed chin

Oval-shaped face with mild bitemporal constriction

Hair

Normal blond straight head hair, hypertrichosis of arms and back

Hypertrichosis with lanugo hair on face

Curly hair

Fine hair

Eyes

Epicanthus, upslanted palpebral fissures

Hyperopia +6.5 D

Slight right epicanthus, wide-set eyes, remarkable broad left eyebrow with long hairs

Wide-set, slight epicanthus, downslanting palpebral fissures

Mild telecanthus, upslanting, short and narrow palpebral fissures hyperopia, mild bilateral optic nerve hypoplasia

Nose

Full nasal tip, prominent columella

Long, smooth philtrum

Prominent columella

Prominent nose with low-hanging prominent columella

Philtrum

Deeply grooved

Smooth

Normal

Smooth

Mouth

Full lower lip

Normal

Wide-set points of upper vermilion

Wide mouth with thin upper vermillion border; highly arched palate, widely spaced teeth of abnormal shape

Ears

Prominent crus helicis of right ear

Large

Low-set and posteriorly rotated

Unusual shape with underfolded helix and prominent anthelix

Jaw

Pointed chin

Slight micrognathia, pointed chin

Pointed chin

Pointed chin with prognathia

Thorax

Normal

Wide-spaced inverted nipples

Normal

Normal

Limbs

Congenital trigger thumb, dysplastic nail of left hallux

Bilateral talipes equinovarus with deeply grooved foot soles

Pedes plani, slight genua valga

Bilateral talipes equinovarus

Genital

Normal

Undescended right testis

Normal

Normal

Puberty

No

No

Early breast development starting at 8 years

No

Epilepsy

No

+ (EEG burst suppression)

No

No

Brain

MRI brain: thin corpus callosum, slightly delayed myelination, suggestion of bilateral parieto-occiptalpolymicrogyria, periventricular hyperintensities

MRI brain: absent corpus callosum, wide lateral ventricles, bleeding

MRI brain: absent corpus callosum, colpocephaly

CT brain: suspected partial deficiency of the rostrum of the corpus callosum; non-specific foci in the left frontal and left occipital skull of unknown etiology. No MRI

Heart

Normal

Open ductus arteriosus, heavy heart – no evidence of cardiomyopathy

Normal

Coarctation of aorta, mitral valve stenosis

Kidneys

Renal ultrasound not done yet

Multicystic dysplastic left kidney, pyelectasia/ hydronephrosis of right kidney

Normal renal ultrasound

Multicystic dysplastic right kidney. History of multiple urinary tract infections. Normal voiding cystourethrogram

Endocrine

Not investigated

Not investigated

Early signs of puberty, growth hormone deficiency

Normal bone age and growth hormone status

Other

Recurrent upper airway infections, delayed intestinal mobility problems, late first tooth eruption > 3 years

Short neck

Frequent rhinitis in the first year

Frequent otitis media status post tympanostomy and tube placement