. 2020 Nov 21;2(1):100015. doi: 10.1016/j.xhgg.2020.100015

Table 1.

Clinical and molecular features of individuals with HDAC4 variants at a major 14-3-3 binding site

Individual #	1	2	3	4	5	6	7
Variant database accession	ClinVar: SCV001427055	DECIPHER: 300920	DECIPHER: 275175	DECIPHER: 286901	ClinVar: SCV000741300.1	ClinVar: SCV000574314.5	ClinVar: SCV001427054
Age	2 years	6 years	20 years	14 years	5 years	5 years	10 years
Gender	female	male	female	male	male	male	female
HDAC4 variant	NM_006037.4: c.731C>A p.(Thr244Lys)	NM_006037.4: c.740A>G p.(Glu247Gly)	NM_006037.4: c.742C>G p.(Pro248Ala)	NM_006037.4: c.743C>T p.(Pro248Leu)	NM_006037.4: c.743C>T p.(Pro248Leu)	NM_006037.4: c.743C>T p.(Pro248Leu)	NM_006037.4: c.743C>T p.(Pro248Leu)
Parental origin	de novo	de novo	de novo	de novo	de novo	de novo	de novo

In silico predictions and scores

CADD	probably deleterious; 32.0	likely deleterious; 28.2	likely deleterious; 25.1	likely deleterious; 27.3.	likely deleterious; 27.3	likely deleterious; 27.3	likely deleterious; 27.3
PolyPhen-2	probably damaging; 1.000	probably damaging; 1.000	probably damaging; 1.000	probably damaging; 1.000	probably damaging; 1.000	probably damaging; 1.000	probably damaging; 1.000
PROVEAN	deleterious; −5.32	deleterious; −6.21	deleterious; −7.10	deleterious; −8.87	deleterious; −8.87	deleterious; −8.87	deleterious; −8.87
SIFT	damaging; 0.000	damaging; 0.000	damaging; 0.003	damaging; 0.001	damaging; 0.001	damaging; 0.001	damaging; 0.001

Development

Age at walking independently	not achieved	not achieved	18 months	not achieved	not achieved	not achieved; walks with assistance	not achieved; walks with assistance
Education		special school	special school from 7 years	special school		kindergarten with special education classes	special school
Speech development	non-verbal	non-verbal; limited use of Makaton	fluent; first words at 18 months	few single words	non-verbal	single words only	few single words

Neurology

Seizures	infantile spasms; multiple seizure types non-responsive to medication	no seizures	generalized, with multiple seizure types and drop attacks from 11 years	generalized tonic-clonic from 9 years		no seizures	no seizures
Central hypotonia	+	+	+	+	+	+	+
Movement disorder		+		+		−
MRI brain	cerebral atrophy; brainstem and cerebellar atrophy; abnormal signal within the gray matter nuclei	some cerebellar atrophy; subtle symmetrical signal abnormality of dorsal pons and midbrain	normal	generalized paucity of cerebral and cerebellar bulk of brain matter	slight enlargement of the lateral and 3^rd ventricles; prominent extra-axial spaces	thin corpus collosum; nonspecific minor ventriculomegaly; cerebral underdevelopment	normal

Facial features

Hypertelorism		+	+		+	−	+
Full lower lip		+	+	+	+	−	+
Widely spaced teeth		+		+	+	−	+
Frontal upsweep of hair	+	−	+	+	+	−	−
Long palpebral fissures		−	+	+	+	+	+
Large ears		−	+	+		−	+

Growth parameters

Height centile		20^th	85^th	3^rd at 5 years	99^th	12^th	5^th
Weight centile		9^th–25^th	99^th	2^nd at 8 years	15^th	17^th	25^th
Head circumference centile		99^th	84^th	29^th at 5 years	51^st	24^th	50^th

Additional features

Feeding difficulties	swallowing difficulties; gastrostomy-fed	poor suck, needs pureed food		swallowing difficulties, soft food, thickened fluids		slow bite and chewing of food; oral aversion	+
Drooling		+	+, preschool years	+	+	+	+
Sleep disturbance		+	+	+		−
Hyperextensibility of finger joints			+	+		−	+
Kyphosis/scoliosis			progressive thoracolumbar scoliosis	kyphosis	scoliosis	postural thoracolumbar kyphosis	scoliosis
Hip anomalies		bilateral femoral head subluxation at 5 years	congenital hip dislocation	congenital hip dislocation		mild lateral subluxation of right hip
Delayed closure of anterior fontanelle		+		+		−
Visual problems	absence of tracking		astigmatism	hypermetropia		intermittent esotropia; hyperopia; astigmatism; amblyopia
Other	apnea; hyperpigmented macule	hydronephrosis; delayed dentition; pectus carinatum; patent ductus arteriosus	severe nut allergy	bilateral talipes equinovarus		asymmetric chest wall; delayed dentition; undescended testis

Note: CADD (Combined Annotation Dependent Depletion) results show classification and Phred scores; PolyPhen-2 (Polymorphism Phenotyping v2) results show classification and score; PROVEAN (Protein Variation Effect Analyzer) and SIFT (Sorting Intolerant From Tolerant) threshold scores for binary classification were −2.50 and 0.05, respectively; + (plus) denotes feature present; − (minus) denotes feature absent; blank cells indicate data not available, not applicable, or not measured.