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Germline mutation in POLR2A: a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation.

ABSTRACT: De novo germline variation in POLR2A was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic de novo or inherited variants in POLR2A, detail their phenotypes, and map all known variants to the domain structure of POLR2A and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by de novo missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance-with yeast functional assays further supporting altered function-one affected by a de novo in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7%) than previously reported (3/15, 20%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7%) than previously reported (14/15, 93.3%) (p value = 0.076309). POLR2A-related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.

SUBMITTER: Hansen AW

PROVIDER: S-EPMC7928427 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveDisruptive mood dysregulation disorder (DMDD) in DSM, characterized by severe, chronic irritability, currently excludes children <6 years of age. However, capitalizing on a burgeoning developmental science base to differentiate clinically salient irritability in young children may enable earlier identification. The objective of this study was to advance an empirically derived framework for early childhood DMDD (EC-DMDD) by modeling and validating DMDD patterns in early childhood and generating clinically informative, optimized behaviors with thresholds.MethodData (N = 425) were from 3 longitudinal assessments of the MAPS Study, spanning preschool (means = 4.7 and 5.5 years) to early school age (mean = 6.8 years). The Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB) Temper Loss scale captured irritability, the Family Life Impairment Scale (FLIS) assessed cross-domain impairment at the preschool time points and the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) was used to assess clinical status at early school age. Latent transition analyses differentiated children with EC-DMDD from children with low, transient, or nonimpairing irritability.ResultsDevelopmental patterning of irritability proved important for normal:abnormal differentiation. Of children, 27% had initially high irritability, but only two-thirds of these were persistently highly irritable. Thus, "false positives" based on a single screen would be substantial. Yet, "false negatives" are low, as <1% of children with baseline low irritability demonstrated later high irritability. Based on the sequential preschool-age time points, 6.7% of children were identified with EC-DMDD, characterized by persistent irritability with pervasive impairment, similar to prevalence at older ages. Specific behaviors included low frustration tolerance; dysregulated, developmentally unexpectable tantrums; and sustained irritable mood, all of which sensitively (0.85-0.96) and specifically (0.80-0.91) identified EC-DMDD. EC-DMDD predicted irritability-related syndromes (DMDD, oppositional defiant disorder) at early school age better than downward extension of DSM DMDD criteria to preschool age.ConclusionThese findings provide empirical thresholds for preschool-age clinical identification of DMDD patterns. The results lay the foundation for validation of DMDD in early childhood and inform revision of DSM criteria.

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Germline mutation in POLR2A: a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation.

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