Table 1.
Variant information and phenotypes of individuals with ultra-rare POLR2A variants
| Individual ID | 1 | 2 | 3 | 4 | 5 | 6 | 7 (Haijes et al.6individual 15) | 8 | 9 | 10 | 11 | 12 | Summary |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Consented to sharing of individual-level phenotypes? | yes | yes | yes | yes | yes | yes | yes | yes | no | no | no | no | NA |
| Sex | F | M | M | M | F | F | F | F | M | F | M | M | NA |
| Age (in years, at requisition or most recent phenotyping) | 0.32 | 4 | 3.5 | 10 | 21 | 6.75 | 11 | 14 | 1.13 | 16.12 | 1.49 | 4.36 | NA |
| Molecular | |||||||||||||
| Previous/additional Molecular Diagnosis | unsolved | unsolved | unsolved | unsolved | unsolved | unsolved | mitochondrial complex IV deficiency indicated via skeletal muscle enzyme analysis; mtDNA sequencing was negative | unsolved | unsolved | unsolved | unsolved | unsolved | NA |
| Chromosome | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | 17 | NA |
| Position | 7401503 | 7411610 | 7411736 | 7412890 | 7412890 | 7415280 | 7416391 | 7417020 | 7388166 | 7399625 | 7399813 | 7411604 | NA |
| Genomic variant | GACCTTC>G | C>T | C>T | A>G | A>G | G>A | G>A | CCA>C | C>G | G>A | C>T | C>T | NA |
| cDNA variant | c.1314_1319del | c.3281C>T | c.3407C>T | c.3752A>G | c.3752A>G | c.4252G>A | c.4808G>A | c.5440_5441del | c.83C>G | c.323G>A | c.418C>T | c.3275C>T | NA |
| Amino acid change | p.Leu438_His439del | p.Ser1094Phe | p.Thr1136Ile | p.Asn1251Ser | p.Asn1251Ser | p.Gly1418Arg | p.Arg1603His | p.Gln1814Valfs99ter | p.Pro28Arg | p.Arg108His | p.Arg140Trp | p.Ala1092Val | NA |
| GERP++ score (conservation) | mean = 4.64 (0.89–5.6; SD = 1.9; 6 bases) | 5.36 | 5.23 | 5.11 | 5.11 | 5.06 | 3.93 | mean = 1.68 (−8.25–4.13; SD = 3.06; 476 bases) | 5.82 | 5.57 | 5.57 | 5.36 | NA |
| MTR score (31 bp) (missense constraint) | mean = 0.675 (0.637–0.678; 2 amino acids) | 0.477 | 0.172 | 0.516 | 0.516 | 0.301 | 1.031 | mean = 0.7 (0.448–0.968; SD = 0.131; 158 amino acids) | 0.598 | 0.649 | 0.673 | 0.528 | NA |
| Zygosity | het | het | het | het | het | het | het | het | het | het | het | het | NA |
| De novo in proband? | yes | yes | yes | yes | yes | yes | yes | no; inherited from mother with mild difficulty learning | ? | ? | ? | ? | NA |
| Yeast variant phenotype | transcription defect (weak) (yeast Ile424Δ corresponds to human p.Leu438del) | ? | ? | ? | ? | transcription defect (slight) | ? | ? | protein defect (strong) | protein defect (weak) | protein defect (strong) | transcription defect (weak) | NA |
| Phenotypes | |||||||||||||
| Short stature (HP:0004322) | + | − | − | − | − | − | 5th percentile | − | 3/4 | 5/12 | |||
| Head and neck | |||||||||||||
| Dysmorphic features (HP:0001999) | + | high anterior hairline; mild downslanting palpebral fissures; strabismus | high anterior hairline; epicanthus; downslanting palpebral fissures; long lateral palpebral fissures; tented upper lip vermilion; prominent ears | prominent supraorbital ridges; high posterior hairline; upslanted palpebral fissures; fair complexion; deeply set eyes; large ear lobes; high palate | broad forehead; bilateral epicanthus; prominent supraorbital ridges; fair complexion; deeply set eyes; strabismus (when tired) | − | prominent ears; thin upper lip vermilion; smooth philtrum | NP | 3/4 | 9/12 | |||
| Abnormal brain MRI (HP:0012443) | polymicrogyria (HP:0002126), ventriculomegaly (HP:0002119), hydrocephalus (HP:0000238), hypomyelination (HP:0006808) | Rathke cleft cyst | − | thin corpus collosum (HP:0002079), mild pontine and interior vermian hypoplasia (HP:0012110, HP:0007068), enlargement of the fourth ventricle (HP:0002198), delayed myelination (HP:0012448) | prominent third and lateral ventricles at 1 year old (HP:0007082, HP:0006956) | − | thin corpus collosum (HP:0002079), ventriculomegaly (HP:0002119), 7 mm cyst in temporal parietal junction, bilateral loss of white matter (HP:0012429) | polymicrogyria involving large portions of left cerebral hemisphere including perisylvian region and portions of the left frontal, parietal, and temporal lobes (HP:0002126); left cerebral atrophy (HP:0002059); small enhancing developmental venous anomaly at right parieto-occipital junction (HP:0012481) | 1/4 | 7/12 | |||
| Microcephaly/ macrocephaly | NP | − | − | significant microcephaly (<2 percentile) | − | − | microcephaly | − | macrocephaly 1/4 | 3/12 | |||
| Visual impairment (HP:0000505) | NP | − | astigmatism, both eyes | bilateral elongation of ocular globes noted on MRI | − | cortical | irregular astigmatism, both eyes | wears glasses since age 2 years, no astigmatism reported | NP | 5/12 | |||
| Hearing impairment (HP:0000365) | NP | − | − | − | − | sensorineural | − | right-side hearing deficit attributed to hemiplegia | NP | 2/12 | |||
| Headache (HP:0002315) | NP | − | − | reported by parents; cannot confirm as individual is non-verbal | − | − | reported by parents; cannot confirm as individual is non-verbal | daily severe headaches | NP | 1/10 | |||
| Central nervous system | |||||||||||||
| Developmental delay (HP:0012758) | + | + | + | + | speech and motor (HP:0000750, HP:0001270) | + | + | speech and motor (HP:0000750, HP:0001270) | 4/4 | 12/12 | |||
| Developmental regression (HP:0002376) | NP | three separate 6-month episodes of regression and plateau | − | possible recent regression | regression at age 16 years attributed to worsening anxiety, with new aggressive behaviors | − | − | no regression, but developed personality changes (HP:0000751) and memory problems (HP:0002354) at age 8 years | NP | 4/12 | |||
| Seizures (HP:0001250) | NP | EEG revealed right centroparietal epileptiform discharges | − | generalized tonic-clonic and absence | during childhood, with no discernable seizures since puberty, no longer on anticonvulsants | absence seizures | + | started at 13 years old | 2/4 | 8/12 | |||
| Intellectual disability (HP:0001249) | NP | + | + | + | + | + | + | mild | 1/4 | 8/12 | |||
| Autism spectrum disorder (HP:0000729) | NP | + | + | + | − | + | + | − | 1/4 | 6/12 | |||
| Hypotonia (HP:0001252) | + | + | + | + | + | + | + | − | 1/4 | 8/12 | |||
| Dystonia (HP:0001332) | NP | − | + | + | − | − | − | hypertonia/spasticity of the right extremities due to hemiplegia (HP:0001276, HP:0004374) | NP | 3/12 | |||
| Neck and back arching in infancy | NP | + | + | − | + | NP | − | − | NP | 3/12 | |||
| Abnormal movements (HP:0100022) | NP | hand flapping | hand flapping, kicking, rubs side of head | head banging | occasional hand flapping | hand flapping | head hitting, stimming arms and legs | − | 1/4 | 7/12 | |||
| Pica (HP:0011856) | NP | eats hair, paper, feces | NP | frequently puts objects in mouth | NP | NP | chews on hands, toes, clothes, paper, furniture, toys | NP | NP | 3/12 | |||
| Ataxia (HP:0001251) | NP | + | + | + | ataxic high-stepping gait | + | + | ataxic gait | NP | 7/12 | |||
| Difficulty sleeping (HP:0002360) | NP | obstructive sleep apnea prior to removal of tonsils and adenoids; sleeps >12 h and exhibits daytime sleepiness | − | + | woke up 10× per night in childhood, current symptoms are occasional and mild | NP | no sleep study, but reportedly very light sleeper | insomnia, takes clonidine for it | NP | 5/12 | |||
| Musculoskeletal | |||||||||||||
| Skeletal abnormality (HP:0000924) | NP | − | − | mild pectus excavatum (HP:0000767), hip dysplasia (HP:0001385), sixth lumbar vertebrae (HP:0008416) | short Achilles tendons have caused foot distortion and difficulty walking (HP:0001771) | NP | hip dysplasia (HP:0001385), pes planus (HP:0001763), leg length discrepancy (HP:0100559) | contractures on right side (HP:0001371), two Achilles tendon release surgeries (HP:0001771) | 1/4 | 5/12 | |||
| Scoliosis (HP:0002650) | NP | − | − | − | − | neurogenic | − | − | NP | 1/12 | |||
| Joint hypermobility (HP:0001382) | NP | + | + | + | − | hyperextensible elbows and knees | + | − | 1/4 | 6/12 | |||
| GI system | |||||||||||||
| Failure to thrive (HP:0001508)/ feeding difficulty (HP:0011968) | + | + | − | poor weight gain but normal linear growth | + | − | + | − | 2/4 | 7/12 | |||
| Uses gastrostomy tube | NP | planned but not yet inserted | − | inserted at 9 years old | − | inserted at 5 years old | − | NP | 3/12 | ||||
| GI reflux (HP:0002020) | NP | + | − | + | + | − | − | + | 1/4 | 5/12 | |||
| Constipation (HP:0002019)/ diarrhea (HP:0002014) | NP | constipation | constipation | constipation | − | − | constipation and diarrhea | − | diarrhea 1/4 | 5/12 | |||
| Other | |||||||||||||
| Urogenital system (HP:0000119) | NP | incontinence | incontinence | neurogenic bladder; incontinence; swollen left kidney after birth; small scrotum, retractile testes | toilet trained at age 6 years, still some incontinence | NP | incontinence | history of several urinary tract infections (HP:0000010) | kidney abnormality 1/4 | 7/12 | |||
| Skin abnormality (HP:0000951) | NP | easy scarring, keratosis pilaris | − | easy scarring | easy scarring | − | keratosis pilaris, facial flushing | − | unspecified abnormality 1/4 | 5/12 | |||
| Immune system (HP:0002715) | NP | neutropenia (HP:0001875); granulocytopenia (HP:0001913); high lymphocyte percentage (HP:0100827) | − | intermittent leukocytosis (HP:0001974) | − (no antibiotics needed for >10 years) | NP | − | − | unspecified abnormality 1/4 | 3/12 | |||
| Fever (HP:0001954) | NP | chronic (HP:0001955) | − | fever of unknown etiology (HP:0001955) | fever of unknown etiology in childhood (HP:0001955) | − | − | − | chronic fever 1/4 | 4/12 | |||
| Cardiac abnormality (HP:0001627) | dilated cardiomyopathy (HP:0001644) | − | Bicuspid aortic valve (HP:0001647) | Atrial septal defect (HP:0001631), congestive heart failure in infancy (HP:0001635) | − | NP | − | − | NP | 3/12 | |||
| Lung abnormality (HP:0002086) | immature lungs (HP:0006703) | recurrent upper respiratory infections (HP:0002788); frequent nebulizer use (budesonide and albuterol) | recurrent upper respiratory infections (HP:0002788); uses inhaler and nebulizer | poor airway clearance requiring vest therapy, suctioning, and cough assist; recurrent upper respiratory infections (HP:0002788) | − | − | recurrent upper respiratory infections (HP:0002788); hospitalized four times for pneumonia, once for bronchiolitis | − | NP | 5/12 | |||
| Congenital diaphragmatic hernia (HP:0000776) | NP | − | − | − | − | − | − | − | 1/4 | 1/12 | |||
| Other | NP | hypothyroidism (HP:0000821); tooth misalignment (HP:0000692); consistently elevated BUN/creatine ratio (HP:0040081), alkaline phosphatase (HP:0004379), and prolactin (HP:0040086) | − | history of angioedema with levetiracetam use (HP:0100665); hemangioma (HP:0001028); 2-vessel umbilical cord (HP:0001195); adverse reaction to therapeutic botulinum toxin; enlarged liver that resolved after birth (HP:0006564); hyponatremia (HP:0002902) | psychosis induced by fluoxetine; agitation with sedatives and general anesthesia | NP | intolerant of wheat and dairy (not allergic); reduced fetal movement (HP:0001558) | − | NP | 4/12 | |||
All variants are considered likely pathogenic. Phenotypes are indicated as either positive, negative, or not phenotyped or reported (NP) for each individual. For research-consented individuals, individual-level phenotypic information is presented. For the four other clinical individuals (individuals 9–12), phenotypic information is presented in aggregate. The summary column indicates how many individuals were positive for a given phenotype. All cDNA variants are based on the NM_000937.4 transcript definition. All genomic coordinates are based on the hg19 genome build. Human Phenotype Ontology (HPO) IDs are indicated for phenotypes where appropriate. +, positive; −, negative; BUN, blood urea nitrogen; het, heterozygous; GI, gastrointestinal; NA, not applicable.