Table 1.
Main Clinical Features of Individuals
| General Information | Individual 1 | Individual 2 | Individual 3 | Individual 4 | Individual 5 | Individual 6 | Individual 7 | Individual 8 | Individual 9 | Individual 10 | Individual 11 | Individual 12 | Individual 13 | Individual 14 | Individual 15 | Individual 16 | Total (Percentage) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age | 6 y | 7 y | 13 y | 3 y, 10 m | 19 y | 2 y, 4 m | 23 y | 2 y, 1 m | 1 y, 9 m | 8 y | 2 y, 4 m | 11 y | 12 m | 4 y | 3 y, 4 m | 7 y | NA |
| Gender | male | female | male | male | female | female | female | Female | male | female | male | male | male | female | male | male | 9 males, 7 females |
| Chr change (hg19) | g.133536680T>C | g.133533511dup | g.133537587del | g.133533469_133533471dup | g.133536124G>A | g.133536680T>C | g.133536096T>A | g.133537652G>A | g.133537645T>C | g.133534840T>C | deletion at chr5: 133,546,961–133,667,321 | g.133537634C>G | g.133537659C>G | g.133541662T>C | g.133541746C>A | g.133536097C>G | NA |
| GenBank: NM_002715.2 | c.572A>G | c.882dup | c.438del | c.922_924dup | c.640 C>T | c.572A>G | c.668A>T | c.373C>T | c.380A>G | c.794A>G | NA | c.391G>C | c.366G>C | c.263A>G | c.179G>T | c.667G>C | NA |
| Protein change | p.His191Arg | p.Arg295∗ | p.Phe146Leufs∗29 | p.Phe308dup | p.Arg214∗ | p.His191Arg | p.Asp223Val | p.Gln125∗ | p.Tyr127Cys | p.Tyr265Cys | NA | p.Asp131His | p.Gln122His | p.Asp88Gly | p.Gly60Val | p.Asp223His | NA |
| Mutation type | missense | nonsense | frameshift | 1 amino acid insertion | nonsense | missense | missense | nonsense | missense | missense | partial deletion | missense | missense | missense | missense | missense | NA |
| Inheritance | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | de novo | NA |
| Other variants?a | − | + | − | − | + | − | + | + | − | − | + | − | + | − | − | − | NA |
| Proposed mechanism | haploinsufficiency of PP2A-B56δ complexes | dominant-negative effect on PP2A-B56δ complexes | haploinsufficiency: null allele (no expression) | dominant-negative effect on all PP2A-B56 complexes | haploinsufficiency: null allele (latent complex with alpha 4) | haploinsufficiency of PP2A-B56δ complexes | unclear | haploinsufficiency: null allele (no expression) | haploinsufficiency of PP2A-B56 and PR72 complexes; dominant-negative effect on PP2A-B55 and PP2A-STRN complexes | haploinsufficiency: significant impairment of any trimer formation | haploinsufficiency (deletion) | haploinsufficiency of PP2A-B56 complexes | haploinsufficiency? | dominant-negative effect on PP2A-B56γ and B56δ complexes | haploinsufficiency: poor expression | unclear | NA |
| Growth | |||||||||||||||||
| Height | +2 SD | +2.5 SD | +1.3 SD | +1.7 SD | −0.2 SD | 0 SD | +0.7 SD | −1.3 SD | +0.4 SD | −2 SD | −3 SD | −1.6 SD | −1.9 SD | −0.8 SD | 0 SD | −2 SD | NA |
| Head circumference | +2.5 SD | +0.5 SD | −1.5 SD | −3.9 SD | NK | −0.2 SD | +2.8 SD | −0.8 SD | −3 SD | −2.3 SD | −3 SD | −1.1 SD | −4.6 SD | <−2 SD | +1.2 SD | 0 SD | NA |
| Weight | −0.2 SD | 0 SD | −1.1 SD | +0.7 SD | >+2.5 SD | NK | NK | −0.6 SD | −0.2 SD | −1.5 SD | −2 SD | −2.1 SD | −1.9 SD | −0.6 | −2 SD | −1.5 SD | NA |
| Neurological | |||||||||||||||||
| DD and ID (degree) | + (mild) | + (severe) | + (mild) | + (moderate) | + (mild to moderate) | + (mild) | + (mild) | + (mild) | + (severe) | + (mild) | + (mild) | + (profound) | + (moderate) | + (severe) | + (mild) | + (severe) | 16/16 (100%) |
| Severe language delay | + | + | + | + | + | NK | − | − | + | + | − | + | NA | + | − | + | 10/14 (71%) |
| Regression | − | − | + | − | − | − | + (after period with psychoses) | − | − | − | − | − | − | − | − | − | 2/16 (13%) |
| Behavioral problems | − | + (automutilation, stereotypic behavior) | + (PDD-NOS) | − | + (ASD, ADHD) | NK | + (ASD, psychoses) | − | − | + (ASD, ADHD) | − | − | − | − | + | + (ASD) | 7/15 (47%) |
| Hypotonia | − | + | + | − | + | − | + (mild) | + | + | + | − | + | + | + | − | + (mild) | 11/16 (69%) |
| Epilepsy (type) | + (related to fever) | + (tonic-clonic seizures, absences) | + (focal left temporal, mostly at night) | − | + (generalized tonic-clonic seizures, absences) | + (related to fever, tonic-clonic seizures) | − | − | − | + (NK) | − | + (staring spells, head drops, and tonic-clonic seizures) | + (focal epilepsy with secondary generalization) | + (generalized tonic-clonic seizures) | − | + (generalized tonic-clonic seizures) | 10/16 (63%) |
| Epilepsy syndrome | NA | epileptic encephalopathy | focal ESES | NA | Jeavons syndrome | NA | NA | NA | NA | NK | NA | hypsarrhythmia (West syndrome) | not specified | not specified | NA | not specified | NA |
| Age of onset | 11 m | 6 m | 10 y | NA | 6 y | NK | NA | NA | NA | 3 y | NA | 8 m | 5 m | 1 w | NA | 1 y | NA |
| Age of offset | 18 m | ongoing | ongoing | NA | ongoing | NK | NA | NA | NA | ongoing | NA | ongoing | ongoing | ongoing | NA | ongoing | NA |
| Brain abnormalities | + (ventriculomegaly) | + (ventriculomegaly, gracile corpus callosum, delayed myelinization) | − | + (posterior hypoplasia of corpus callosum, unmyelinated left temporal lobe, nonspecific periventricular white-matter hyperintensities) | − | + (mildly underdeveloped pons, mesencephalon, mild dilated lateral and third ventricles) | − | + (reduced white matter [supratentorial and infratentorial], some global atrophy of the brain [pons and corpus callosum], bilateral plexus choroideus cysts) | + (pontocerebellar hypoplasia, mild ventriculomegaly) | + (nonspecific thinning of the corpus callosum, mild volume loss of the cerebellum) | NK | − | + (microcephaly, enlarged subarachnoid spaces, nonspecific findings of cerebral underdevelopment) | + (slightly dilated external and internal subarachnoid spaces, diffuse but discrete atrophy, adequate myelination) | − | + (bilateral dilatation of perivascular spaces along the corona radiata) | 10/15 (67%) |
| Other | − | sleeping difficulties | − | − | burning pain from neck down to left leg | − | − | broad-based gait | optic-nerve anomaly | NK | − | choreiform movements | − | stereotypic movements | − | − | 6/15 (40%) |
| Facial | |||||||||||||||||
| Eyes | hypertelorism, prominent eyes | − | periorbital fullness restricted to upper eyelids, long eyelashes | ptosis, short palpebral fissures | − | prominent eyes, epicanthic folds | small palpebral fissures, deep-set eyes | megalocornea | bilateral epicanthal folds | − | periorbital fulness, upslanting palpebral fissures | − | − | almond-shaped eyes | − | − | NA |
| Nose | full nasal tip, low-hanging columella | broad nasal bridge | full nasal tip | broad nasal tip | − | − | broad nasal tip | asymmetrical nostrils and bifid nasal tip | − | − | − | − | − | − | broad nasal tip, small alae nasi | − | NA |
| Philtrum | short philtrum | short philtrum | − | short philtrum | − | − | − | − | − | − | − | − | − | − | − | − | NA |
| Other dysmorphic features | broad forehead, frontal bossing, square shape of both ears | open fontanel, plagiocephaly, some frontal bossing, prominent upper lip, sacral dimple | − | trigonocephaly, double hair whorl, high palate, low-set and anteverted ears, retrognatia | crowded teeth | plagiocephaly | broad forehead, freckling around the mouth | plagiocephaly | prominent metopic suture, mild micrognathia | − | full cheeks, thin upper lip, everted lower lip, square configuration of the lobule of the ear (right bigger than left) | high arched palate | − | small mouth, high palate | − | − | NA |
| Other | |||||||||||||||||
| Extremities | single left palmar crease, long fingers and toes, bilateral sandal gap | bilateral fetal finger pads, single left palmar crease | − | poorly developed flexure fold on the third right finger, incomplete single transverse palmar crease, adducted thumbs (reducible); X-ray: ovoid appearance of vertebrae, coxa valga, slender distal phalanges | hypermobile knees | mild shortened fifth digits | − | hyperlaxity | bridged palmar crease, bilateral ulnar deviation of wrists and fingers, partially adducted thumbs, right hand greater than left | NK | bilateral fifth-finger clinodactyly | hyperlaxity | bilateral single palmar crease, bilateral adducted thumb | atypical single left palmar crease, pes planus, overlapping toes | single left palmar crease | − | NA |
| Feeding difficulties | + | + | + | − | − | − | − | − | + | NK | + | + | + | + | + (infancy) | − | 9/15 (60%) |
| Vision problems | − | − | − | − | periods of sudden vision loss and pain in left eye | megalocornea, moderated excavated papillae, mild hypermetropia (both eyes +2) | NK | megalocornea, strabismus | CVI | NK | immature retina at the age of 1 m | does not track or blink to threat | − | − | − | − | 6/14 (43%) |
| Other | 4 café-au-lait spots (max 5 mm) | − | vitamin B12 deficiency | elevated right diaphragm | recurrent ear and urinary-tract infections, heart murmur, fractures after minimal trauma | diastasis recti | frequent airway infections as a child | muscular ventricular septal defect | mild bilateral sensorineural hearing loss | NK | inguinal hernia, umbilical hernia | constipation, atrial septal defect, low bone mineral density | trileaflet aortic valve, multiple café-au-lait macules | − | sacral haemangioma | − | NA |
Abbreviations are as follows: +, present; −, not present; w, weeks; y, years; m, months; NK, not known; NA, not applicable; SD, standard deviation; DD, developmental delay; ID, intellectual disability; PDD-NOS, pervasive developmental disorder not otherwise specified; ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; ESES, electrical status epilepticus during sleep; CVI, cerebral visual impairment.
a
Additional information on variant(s) in other gene(s) is in the Supplemental Note.