Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features

Abstract

Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

Mutations in NCAPG2 Cause a Severe Neurodevelopmental Syndrome that Expands the Phenotypic Spectrum of Condensinopathies

“…First, we focused on microcephaly, a feature shared by the probands from families 1 and 2 and a phenotype shown to be experimentally tractable in zebrafish. [62][63][64][65] We identified the sole NCAPG2 ortholog in the zebrafish genome (46% identity, 64% similarity; Figure S4A). Consistent with human expression data (GTEx; Human Protein Atlas), ncapg2 is expressed nearly ubiquitously, and predominant expression is in the developing brain and spinal cord of larval zebrafish.…”

“…ncapg2 Disruption Results in Concomitant Cell Death and Aberrant Mitotic Progression In Vivo Work in model organisms has shown apoptosis or dysregulated cell proliferation to be pathognomonic of neuroanatomical defects. 10,62,63 Additionally, mice lacking Ncapg2 show embryonic lethality between embryonic day (E) 8.5 and E10.5 as a result of increased apoptosis in blastocysts (Table S1). 57 To investigate the underlying cellular basis of head-size reduction in ncapg2 zebrafish models, we performed TUNEL and PH3 staining.…”

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies syndrome due to disruption of BPTF in a 35‐year‐old man initially diagnosed with Silver‐Russell syndrome

“…Using fluorescence in situ hybridization (FISH), whole‐genome and Sanger sequencing we found that the 17q24.2 breakpoint maps at chr17:65,947,981‐65,952,868 (hg19) (deletion of 4.9 kb) in intron. 25 of the dosage sensitive Bromodomain PHD finger transcription factor ( BPTF ) gene (NM_004459.6) (pLI = 1.00) (Figure J,K), recently described as responsible for Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) (MIM#617755) . The 1q24.3 breakpoint maps to chr1:172,228,493‐172,234,072 (deletion of 5.5 kb) within the loss‐of‐function tolerant (pLI = 0.03) brain specific DNM3 .…”

“…Psychomotor and speech delay, dysmorphism, and limbs anomalies are similar to the features reported in the NEDDFL subjects . We propose that BPTF testing should be considered in the diagnostic workup of SRS. This is the first description of NEDDFL phenotype in the adult person.…”

Measuring “Intolerance to Mutation” in Human Genetics

“…The pLI measure has been broadly applied in human genetics to help identify genes in which a single disrupting mutation is likely of clinical significance 4,[38][39][40][41][42][43][44][45] . pLI is also increasingly used in clinical annotation and in databases of mouse models as indicative of haploinsufficiency and dosage sensitivity [46][47][48][49][50] .…”