Table 1.
Characteristics of Individuals Harboring a Heterozygous De Novo Variant in POLR2A
| Individual | 5 | 6 | 8 | 12 | 13 | 1 | 16 |
|---|---|---|---|---|---|---|---|
| Variant | p.Gln700∗ | p.Gln735∗ | p.Ser755del | p.Leu1124Pro | p.Lys1125del | p.Pro371Leu | p.Pro1767fs |
| Sex | m | f | m | f | m | f | m |
| Gestation (weeks) | 42 | 28 | Term | 38 | 37 | 41 | 41 |
| Age (years) | 17 | 13 | 3 | 4 | 7 | 7 | 9 |
| General hypotonia | − | + | + | + | + | + | + |
| Strabismus | − | + | + | + | + | + | − |
| Frog position infancy | − | − | + | + | − | − | − |
| Decreased endurance | − | − | + | + | + | − | + |
| Feeding difficulties | − | + | − | + | − | + | + |
| Recurrent RTI | − | − | + | + | − | − | + |
| High forehead | + | + | + | − | + | − | + |
| Disturbed sleeping | + | − | − | − | − | − | − |
| Gastro-esoph. reflux | − | + | − | − | − | − | − |
| High palate | + | − | − | − | + | NA | − |
| Delayed visual matur. | + | − | − | − | − | − | − |
| Microcephaly | − | − | − | − | − | − | − |
| Brachyplagiocephaly | − | − | − | − | + | − | + |
| Muscle atrophy | − | − | − | − | − | − | − |
| Hypertelorism | − | − | − | − | + | + | + |
| Teeth misalignment | − | + | − | + | + | − | + |
| Decreased vision | + | − | − | − | − | + | − |
| Stagnation episodes | − | − | − | − | − | − | − |
| Inguinal hernia | − | − | − | − | − | − | − |
| Decreased fetal movem. | − | − | NA | + | − | − | − |
| Autistic behavior | + | − | − | NA | − | − | − |
| Aggressive behavior | − | − | − | − | − | − | − |
| Failure to thrive | − | − | − | − | − | + | − |
| Pectus excavatum | − | − | − | − | − | − | − |
| Epilepsy | − | − | − | − | − | − | − |
| Sit, no support (months) | 7 | 12 | NA | 12 | 18 | 24 | 24 |
| Walk well (months) | 18 | 30 | >36 | 23 | 24 | 72 | 28 |
| Brain MRI abnormalities | − | Cerebellar atrophy, inferior vermis, small pons, megacisterna magna, and slightly small corpus callosum | Delayed myelination | Delayed myelination | Delayed myelination | − | − |
| Severity score | 6 | 9 | 9 | 9 | 10 | 11 | 11 |
| Severity class | Mild | Mild | Mild | Mild | Mild | Mild | Mild |
| Individual | 4 | 11 | 10 | 15 | 9 | 14 | 2 | 7 | 3 |
|---|---|---|---|---|---|---|---|---|---|
| Variant | p.Tyr669del | p.Tyr1109His | p.Ile848Thr | p.Arg1603His | p.Met769Thr | p.Asn1251Ser | p.Ile457Thr | p.Thr736Met | p.Asn531Ser |
| Sex | f | m | f | f | m | f | m | f | m |
| Gestation | 41 | 40 | 41 | Term | 41 | 40 | 40 | 39 | 30a |
| Age (years) | 11 | 6 | 13 | 7 | 18 | 6 | 4 | 9 | 0 |
| General hypotonia | + | + | + | + | + | + | + | + | NA |
| Strabismus | − | + | − | + | + | + | + | + | NA |
| Frog position infancy | + | + | + | + | + | + | + | + | NA |
| Decreased endurance | + | NA | + | − | + | + | + | + | NA |
| Feeding difficulties | + | − | + | − | + | + | + | + | NA |
| Recurrent RTI∗ | − | + | − | + | − | + | + | + | NA |
| High forehead | − | − | − | − | + | − | + | − | − |
| Disturbed sleeping | + | − | − | + | + | + | + | + | NA |
| Gastro-esoph. reflux | + | − | + | − | − | + | + | + | NA |
| High palate | − | − | − | − | + | − | + | + | Cleft |
| Delayed visual matur. | + | − | − | + | + | − | + | + | NA |
| Microcephaly | − | + | − | + | + | + | − | + | − |
| Brachyplagiocephaly | − | − | + | − | − | + | + | − | − |
| Muscle atrophy | − | − | + | − | + | − | + | + | NA |
| Hypertelorism | − | − | − | − | + | − | + | − | + |
| Teeth misalignment | + | − | − | − | − | − | − | − | − |
| Decreased vision | − | − | − | + | + | − | − | + | NA |
| Stagnation episodes | + | + | − | − | − | − | + | + | NA |
| Inguinal hernia | + | − | − | − | + | − | + | + | NA |
| Decreased fetal movem. | − | − | − | − | − | + | + | − | − |
| Autistic behavior | + | − | − | + | + | − | − | − | NA |
| Aggressive behavior | + | − | + | + | − | + | − | − | NA |
| Failure to thrive | − | − | − | − | − | + | − | + | NA |
| Pectus excavatum | + | − | − | − | + | + | − | − | NA |
| Epilepsy | − | + | − | + | − | − | − | + | NA |
| Sit, no support (months) | 11 | 24 | 24 | Attained | 14 | 48 | 23 | >108 | |
| Walk well (months) | 26 | >72 | >156 | 56 | 27 | 65 | >55 | >108 | |
| Brain MRI abnormalities | − | Wide ventricles, increased T2 signals in nuclei pallidi | Wide ventricles, cystic area in periventricular white matter | Wide ventricles, thin corpus callosum, bilateral loss of white matter | Delayed myelination | Megacisterna magna | Delayed myelination, wide ventricles | Wide ventricles and sulci, cerebellar volume loss, abnormal globus pallidus | Corpus callosum agenesis |
| Severity score | 14 | 14 | 15 | 16 | 19 | 21 | 23 | 25 | NA |
| Severity class | Moderate | Moderate | Moderate | Moderate | Severe | Severe | Severe | Profound | |
Abbreviations are as follows: m = male, f = female, NA = not available, and RTI = respiratory tract infections.
a
Termination of pregnancy.