Table 1.
Clinical and genetic information of patient series
| Patient # | 1 | 2 | 3 | 4 |
| Age (years) | 15 years old | 2.5 years old | 14 years old | 5 years old |
| Gender | Male | Male | Male | Male |
| Country | United States | Jordan | USA | USA |
| Ancestry | Old Order Amish | Jordanian | Hispanic | European |
| Variant information | ||||
| PPP1R3F variant | c.140C > A; p.Pro47Gln | c.446C > G; p.Pro149Arg | c.634G > T; p.Gly212Ter | c.910C > T; p.Gln304Ter |
| Variant coordinate (hg38) | chrX:49270009(C > A) | chrX:49270315(C > G) | chrX:49270503(G > T) | chrX:49270779(C > T) |
| Zygosity | Hemizygous | Hemizygous | Hemizygous | Hemizygous |
| Allele Freq | gnomAD 0.00% | gnomAD 0.00% | gnomAD 0.00% | gnomAD 0.00% |
| Polyphen2 | probably_damaging | probably_damaging | na | na |
| Provean | neutral | neutral | na | na |
| SIFT | tolerated | damaging | na | na |
| MutationTaster | polymorphism | disease_causing | disease_causing | disease_causing |
| CADD score | 23.7 | 24 | 37 | 35 |
| Other genetic findings | Normal CMA | Normal karyotyping | SMARCC2 variant (de novo) c.230C > T (p.Pro77Leu), normal CMA and exome array | SMARCC2 variant (de novo) c.230C > T (p.Pro77Leu), normal Fragile X test, normal CMA and exome array |
| Clinical findings | ||||
| Learning disability (HP:0001328) | Yes; ‘slow processing’ | Yes | Yes | Yes |
| ID (HP:0001249) | Yes; mild | Yes; mild | Yes; mild | No |
| Speech delay (HP:0000750) | Yes; especially expressive language | Yes; delayed speech | Yes, expressive language delay | Yes; delayed speech |
| Behavioral disorder | Yes; aggressive behavior (HP:0000718) | NA | Yes; ADHD (HP:0007018) | No |
| Neurological findings | Unsteady gait with increased deep tendon reflexes of lower extremities (HP:0002317, HP:0001347) | Mild hyperkinesia (HP:0002487) | Gross motor DD (HP:0002194), mixed hyper-hypotonia with brisk reflexes and abnormal gait (HP:0001276, HP:0001252, HP:0001348, HP:0001288) | Gross motor DD (HP:0002194); history of hypotonia and reduced core strength (HP:0001252). |
| Seizures | Generalized, mostly nocturnal, onset at 3 years old, controlled with valproic acid (HP:0002197) | No seizures (Normal EEG) | Abnormal EEG with no seizure (HP:0002353) | No seizures (Normal EEG) |
| Brain imaging | Normal MRI at 4 years old | Normal MRI | Normal MRI | Normal MRI at 2 years old. Spine MRI at 4 years old showed hydromyelia (HP:0100565) from T7 to L1, and intrasacral meningocele (HP:0005765) at S3. |
| Dysmorphic Features | No | Uplifted ear lobe (HP:0009909) | Relative microcephaly (HP:0000252), hypotelorism (HP:0000601), broad nasal tip (HP:0000455), hypoplastic philtrum (HP:0005326), narrow philtrum (HP:0011829), posteriorly rotated ears (HP:0000358), everted lower lip vermilion (HP:0000232), thin upper lip vermilion (HP:0000219) | Very sparse hair growth over temples (HP:0008070), hooded eyelids (HP:0030820). |
| Other | Occasional tremors (HP:0001337), nocturnal enuresis (HP:0010677) | Normal hearing assessment | Short stature (HP:0004322), bruising susceptibility (HP:0000978), dental crowding (HP:0000678), dry skin (HP:0000958), hypercalciuria (HP:0002150), joint hypermobility (HP:0001382), ligamentous laxity (HP:0001388), limb pain (HP:0009763), pes planus (HP:0001763), thoracolumbar scoliosis (HP:0002944). | Chronic fatigue (HP:0012432), exercise intolerance (HP:0003546), oculomotor apraxia (HP:0000657). Tethered cord syndrome and syringomyelia (repaired) with residual chronic left sided weakness (leg > arm) (HP:0002144, HP:0003396). Mother with seizures and math learning disabilities. |
| 6 | 7 | 8 | 9 | 10 |
| 3 years old | 15 month | 15 years old | 33 years old | 13 years old |
| Male | Male | Male | Male | Male |
| Germany | China | USA | The Netherlands | Turkey |
| Russian | East Asian | European | Dutch | Turkish |
| c.121G > T;p.Asp41Tyr | c.835C > G; p.Arg279Gly | c.538C > T; p.His180Tyr | c.317C > T, p.Pro106Leu | c.1290dupC; p.Arg431Glnfs*34 |
| chrX:49269990(G > T) | chrX:49270704(C > G) | chrX:49270407(C > T) | chrX:49270186(C > T) | chrX:49285980(insC) |
| Hemizygous | Hemizygous | Hemizygous | Hemizygous | Hemizygous |
| gnomAD 0.00% | gnomAD 0.0006% | gnomAD 0.00% | gnomAD 0.00471%, 1 hemizygote | gnomAD 0.00% |
| probably_damaging | possibly_damaging | probably_damaging | benign | na |
| deleterious | neutral | neutral | neutral | na |
| damaging | tolerated | tolerated | damaging | na |
| disease_causing | polymorphism | polymorphism | disease_causing | na |
| 24.1 | 23.8 | 21.9 | 21.7 | disease_causing |
| Conventional karyotyping, CMA, Fragile X and Angelman syndrome testing are all normal | Normal CMA, a homozygous variant in EFCAB8 and compound heterozygous variants in CBY2 | Exome sequencing detected no known copy number variations. Exome SNP analysis normal | SNP array revealed a paternally inherited 15q11.2 microdeletion. Normal Fragile X test. | Conventional karyotyping and CMA were normal |
| Yes | Yes | Yes; cognitive delay and autism | Yes | Yes |
| (too young to evaluate) | Yes; mild | Yes | Yes; severe | Yes; severe |
| Yes; absent speech, nonverbal | Yes; absent speech | NA | NA | Yes; absent speech, nonverbal (HP:0001344) |
| Yes; ASD (HP:0000729) | NA | Yes; aggressive behavior (HP:0000718) | Yes; aggression fits, bites hands when tense, otherwise social and friendly (HP:0000718) | Yes; hand flapping (HP:0100023) |
| Oral motor weakness (HP:0030190) | Spastic-dystonic quadriplegic cerebral palsy (HP:0002510, HP:0100021) | No | Yes; pyramidal signs (HP:0007256) | Spastic paraplegia (HP:0001258) |
| No seizures (Normal EEG) | No seizures | Abnormal EEG (HP:0002353), variable: generalized tonic, atonic, myoclonic and absence, onset at 2.5 years old (HP:0001250); intractable. | No seizures | Complex focal seizures (HP:0002384), onset at 6 years old, controlled with lamotrigine and perampanel |
| Unremarkable MRI; small subependymal hemorrhage on the right side by brain ultrasound | Normal MRI | Abnormal; interval diffuse volume loss and thinning of the corpus callosum (HP:0033725) | NA | Abnormal; temporal hyperintensity, arachnoid cyst (HP:0410263, HP:0100702) |
| Depressed nasal bridge (HP:0005280), epicanthus (HP:0000286), anteverted nares (HP:0000463), prominent lips (HP:0012471), widely spaced nipples (HP:0006610), mild clinodactyly of the fourth and fifth fingers (HP:0030084) | NA | No | Coarse facial features (HP:0000280), prominent supraorbital ridge (HP:0000336), thick eyebrows (HP:0000574), brachycephaly (HP:0000248), small deep set eyes (HP:0000490), short nose with broad nasal tip (HP:0000455), hypoplastic midface (HP:0011800), short philtrum (HP:0000322), large chin (HP:0011822), small ears with overfolded helix (HP:0008551), coarse hair (HP:0002208), thick neck (HP:0000475), dry skin (HP:0000958) | Microcephaly (HP:0000252), brachycephaly (HP:0000248), coarse facies (HP:0000280) from age 12 years old, bushy eyebrows (HP:0000574), prominent mouth, short philtrum (HP:0000322) |
| Sleep disorder (HP:0002360) | Microcephaly (HP:0000252) | Mother with history of a couple of generalized tonic–clonic and myoclonic seizures as a child, controlled with antiepileptic meds for 3 years, was weaned off meds and no seizures since. | Short stature (HP:0004322), deafness (HP:0000365), myopia (HP:0000545), scoliosis (HP:0002650), progressive flexion contracture of the fingers (HP:0005876), camptodactyly (HP:0012385) which seems progressive, pes planus (HP:0001763) and stiff feet, kyphosis (HP:0002808), scoliosis (HP:0002650), female fat distribution (HP:0007552) | Short stature (HP:0004322), ventricular septal defect (HP:0001629), valvular pulmonary stenosis (HP:0034350) |
| 11 | 12 | 13 | ||
| 5 years old | 5 years old | 6 years old | ||
| Male | Male | Male | ||
| Suriname | Egypt | Germany | ||
| South East Asian | Egyptian | European | ||
| c.244G > T; p.Asp82Tyr | c.1187A > T; p.Asp396Val | c.207_228del, p.Gly70AlafsTer95 | ||
| chrX:49270113(G > T) | chrX:49285877(A > T) | chrX:49270078(del22bp) | ||
| Hemizygous | Hemizygous | Hemizygous | ||
| gnomAD 0.00506% | gnomAD 0.00% | gnomAD 0.004935%, 1 hemizygote | ||
| possibly_damaging | probably_damaging | na | ||
| neutral | deleterious | na | ||
| damaging | damaging | na | ||
| polymorphism | disease_causing | na | ||
| 25.6 | 22.8 | disease_causing | ||
| Normal CMA | No copy number variations in exome analysis | Conventional karyotyping, CMA, Fragile X and a multi-gene panel testing all gave normal results | ||
| Yes; moderate | Yes | Yes | ||
| Not formally tested | Yes; moderate | Yes, mild | ||
| Yes; no speech development (HP:0001344) | Yes; absent speech (HP:0001344) | Yes | ||
| Yes; ASD (HP:0000729) | NA | Yes, ASD (HP:0000729) | ||
| Mild/moderate motor delay (HP:0001270) | Hypertonia mainly in lower limbs and brisk reflexes (HP:0001276, HP:0001348) | Muscular hypotonia (HP:0001252), fatigability (HP:0012378), uses wheelchairs for longer distances | ||
| Atypical febrile seizures with normal EEG, onset at 1.5 years old. No AED required. (HP:0002373) | Focal-myoclonic; Generalized (HP:0011166) | Myoclonic seizures, atypical absences, onset at 1 year 8 months, initially frequent and fever associated, currently controlled with valproic acid and sultiame (HP:0032794) | ||
| Decreased volume of occipital white matter and some signal intensity changes at FLAIR at 2 years old (HP:0410263) | Mild cortical atrophy, deep Sylvian fissures, bilateral high signal at T2 in putamen, mild deep white matter signal, thin body of corpus callosum, cerebellar atrophy mainly vermis (at 2–3 years old) (HP:0410263, HP:0002120, HP:0001272) | Normal MRI at 3 years old | ||
| Microcephaly (HP:0000252), deep set eyes (HP:0000490), prominent cheeks | Long face (HP:0000276), hairy forehead (HP:0011335), straight palpebral fissures (HP:0008050), prominent nasal root (HP:0000426), hypoplastic alae nasi (HP:0000430), long philtrum (HP:0000343), v-shaped upper lip, everted lower lip (HP:0000232), pointed chin (HP:0000307), low set ears (HP:0000369) | Mild dysmorphic features (HP:0001999), macrocephaly (HP:0000256) with prominent forehead (HP:0011220), hypertelorism (HP:0000316), small mouth (HP:0000160), short philtrum (HP:0000322) | ||
| Short stature (HP:0004322), prematurity, growth retardation (HP:0008897), conductive hearing loss (HP:0000405) | Nystagmus at 3 ms old (HP:0000639), occasional tremors (HP:0001337), unsteady, upward gaze, rigidity (HP:0002063), after experienced epilepsy he fairly followed objects or reacted to surrounding, underweight (HP:0004325), right undescended testis (HP:0000028) | Pectus excavatum (HP:0000767), Kyphosis (HP:0002808), Pes planus (HP:0001763), sleep disturbance (HP:0002360) |
CMA, chromosome microarray; N/A, not analyzed.