Combined homozygous HACE1 and TBCD variants in two siblings with severe early-onset neurodevelopmental disorder: Two case reports

Table 1 Comparison of clinical features in patients homozygous for the HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 c.625C>T (p.Gln209*) variant

	Clinical features of SPPRS (OMIM #616756)	Patient from Nagy et al[8], 2019	Proband (III-5)	Proband’s younger brother (III-6)
Ethnicity/origin	Pan-ethnic	Saudi Arabia	Chechen	Chechen
Sex	Males and females	Female	Male	Male
Age at presentation	Infancy/early months	5 years 4 months	3 years 10 months	2 years 2 months
Neurology
Sitting and walking	Unsteady waddling gait; inability to walk	Not achieved at 5 years	Not achieved at 3 years	Not achieved at 2 years
Expressive speech	Poor or severely delayed	Absent at 5 years	Absent at 3 years	Absent at 2 years
Developmental delay	Present (severe)	Present	Present	Present
Epilepsy	Seizures (in some patients)	Absent	Present (early-onset epileptic encephalopathy)	Absent
Mobility	Hypotonia; spasticity; ataxia	Hypotonia	Hypotonia evolving into spasticity	Hypotonia
Ophthalmic findings	Strabismus; myopia; retinal dystrophy	Retinal dystrophy	Partial bilateral optic nerve atrophy	Not reported
Hearing	Sensorineural hearing loss (in some patients)	Bilateral sensorineural loss noted at 4 years	Normal	Not reported
Intellectual disability	Present	Present	Present	Present
Brain MRI	Hypoplastic corpus callosum; cerebral atrophy; delayed myelination; decreased white matter volume	Microcephaly and brachycephaly; hypoplastic corpus callosum and likely brainstem abnormality; small sella with ectopic neurohypophysis; mild ventriculomegaly	Progressive cerebral and cerebellar atrophy; thinning of the corpus callosum; cystic changes and gliosis in the left frontoparietal region; ventriculomegaly	Hypoplastic corpus callosum; mild periventricular white matter changes; mixed hydrocephalus
Gastrointestinal	Not reported	Intestinal pseudo-obstruction; neurogenic bladder and bladder stoma	Severe dysphagia; feeding difficulties; protein-energy malnutrition	Feeding difficulties
Skeletal	Kyphosis; scoliosis; hip dislocation; foot deformities	Bilateral hip dislocation; thoracolumbar kyphoscoliosis; ulnar deviation of the wrists, small feet	Normal	Normal
Endocrine	Not reported	Hypothyroidism; adrenal insufficiency	Not reported	Not reported
Facial features	No consistent dysmorphism	Downturned mouth	Normal	Normal

MRI: Magnetic resonance imaging; SPPRS: Spastic paraplegia and psychomotor retardation with or without seizures.

Table 2 Computational pathogenicity scores and calibrated thresholds for the tubulin-specific chaperone D c.2139T>A (p.His713Gln) variant

Tool	Score	Prediction	Threshold
AlphaMissense	0.1353	Benign	0-0.33[9]
REVEL	0.162	Benign moderate	0.016-0.183[10]
CADD (v1.7)	0.395 (PHRED)	Benign moderate	0.15-17.3[10]
PolyPhen	0.007	Benign moderate	≤ 0.009[10]
SIFT1	0.01	Indeterminate	0.080-0.327 (benign supporting); 0-0.001 (pathogenic supporting)[10]
PANTHER	30 my (0.13 Pdel)	Probably benign	Time < 200 my[11]

¹SIFT result was flagged as “low confidence” due to limited sequence alignment depth.

PHRED: PHRED-scaled score; Pdel: Probability of deleterious effect; my: Million years.