BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations

Abstract

An increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.a. Dias-Logan syndrome) ascertained through an international collaborative network, and reviewed 35 additional previously reported patients. Analysis of 77 affected individuals identified 60 unique disease-causing variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique BCL11A microdeletions. We define the most prevalent features of BCL11A-IDD: IDD, postnatal-onset microcephaly, hypotonia, behavioral abnormalities, autism spectrum disorder, and persistence of fetal hemoglobin (HbF), and identify autonomic dysregulation as new feature. BCL11A-IDD is distinguished from 2p16 microdeletion syndrome, which has a higher incidence of congenital anomalies. Our results underscore BCL11A as an important transcription factor in human hindbrain development, identifying a previously underrecognized phenotype of a small brainstem with a reduced pons/medulla ratio. Genotype-phenotype correlation revealed an isoform-dependent trend in severity of truncating variants: those affecting all isoforms are associated with higher frequency of hypotonia, and those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S), are associated with higher frequency of postnatal microcephaly. With the largest international cohort to date, this study highlights persistence of fetal hemoglobin as a consistent biomarker and hindbrain abnormalities as a common feature. It contributes significantly to our understanding of BCL11A-IDD through an extensive unbiased multi-center assessment, providing valuable insights for diagnosis, management and counselling, and into BCL11A's role in brain development.

Fig. 1. BCL11A genomic variants.

BCL11A genomic variants annotated to MANE select BCL11A-XL (A), BCL11A-L (B) and BCL11A-S (C) isoforms. Stop gain: red square; frameshift: red triangle, with downstream premature termination codon as small red square; missense variants: yellow triangle; splice variants: light blue triangle. Light blue outline on red triangle: frameshift and potential splice variant ClinVar_VCV000987092.1; light blue outline on yellow triangle: missense and potential splice variant ClinVar_VCV000987093.1 (see Supplementary Table 2). Green: C2H2 DNA binding zinc finger domains. Dark gray bars: regions of predicted NMD escape by “start proximal” and “last exon junction” mechanisms. Purple bar: region of putative interaction with TBR1 (den Hoed et al. [37]). This figure was generated in collaboration with the Decipher team (https://deciphergenomics.org).

Fig. 2. Neuroradiological features of individuals with BCL11A-IDD.

Sagittal (A), Coronal (B) and axial (C) 3D T1 weighted-images (WI) in P35 showing inferior vermian hypoplasia (long arrows in A and B) with associated enlargement of the tegmento-vermian, mild reduction in size of the posterior aspect of the corpus callosum (short arrow in A), hypoplasia of the left cerebellar hemisphere (dashed arrow in B) and mild dysplasia of the vermis (arrowhead in C). Sagittal T1 WI (D) and coronal T2 WI (E) in P25 and sagittal T1 WI in P8 (F) showing isolated vermian hypoplasia with associated enlargement of the tegmento-vermian. Vermian hypoplasia was confirmed with measurements compared to normal values described in Jandeaux et al. [26]. The pons is small in both patients. Sagittal T1 WI in P35 (G), P41 (H), and P17 (I) showing the short pons and abnormally elongated medulla. Normal control for comparison on the bottom right (J).

Fig. 3. BCL11A expression in developing human cerebellum.

Immunohistochemistry of human fetal cerebellum at 12 (A), 16 (B) and 18 (C) weeks post conception. CH cerebellar hemisphere, V developing vermis (with island like fissures); filled arrow, Purkinje cells; open arrow, cerebellar granule neuron precursors; EGL external granule layer, PCL Purkinje cell layer, IGL internal granule layer, GN granule neurons. Bars: gray, 200 µm; white, 100 µm; yellow, 50 µm. D BCL11A normalized gene expression by cell type in developing human cerebellum (data from Aldinger et al. [30]). RPKM, reads per kilobase of transcript per million mapped reads.

Fig. 4. Physical features of individuals with BCL11A-IDD in the present cohort.

A Facial features of selected individuals with BCL11A pathogenic variants, grouped according to variant class (see methods). Patient number is indicated in the bottom right of each image. Approximate ages at time of photographs (y, years; m, months): P1, 42 y; P9, 3y2m; P19, 16 y; P26, 4y6m; P32, 18 y; P36, 11y2m (left), 12y10m (right); P37, 16 y; P41 3y3m (left), 7y8m (right). Additional photographs of the face (profile) and limbs are available in Supplementary Fig. 2. PTV: Protein Truncating Variants (PTVa, type a; PTVb: type b); MISS: missense variants; CNV: Copy Number Variants. No photographs are available for patients with splice-site variants. B GestaltMatcher comparison of the distance distribution among BCL11A-IDD individuals (orange), the random selection from the subjects with 328 disorders (red), and the selection with the same disorder (blue). The black vertical line is the threshold that classifies whether it is the same disorder or random selection. 34.5% of the BCL11A distribution is below the threshold, indicating only a small portion of BCL11A individuals presenting similar facial gestalt. C Distribution of growth parameters (standard deviations, SD) of present cohort (a single value for each individual is represented); lines indicate median, upper and lower quartiles; *** unpaired t-test p = 0.0001. n = 13 HC birth; n = 35 HC; n = 34 height; n = 33 weight. D Head circumference (HC) at birth and postnatal (SD for age and sex) for individuals in present cohort and previously reported where both measurements available; n = 15 (13 PTV, 1 SPL (splice), 1 CNV); paired t-test: ***p < 0.0001. E Head circumference SDs for individuals in present cohort (PTVa, n = 11; PTVb, n = 18; MISS, n = 3); lines indicate median, upper and lower quartiles; unpaired t test: *p = 0.0083; ns not significant. F Circular bar plot representing frequencies for phenotypic features in the present cohort; bars are proportional to frequency, 25% intervals indicated by ticks. DD developmental delays, IDD intellectual developmental disorder, ASD autism spectrum disorder, abn. abnormalities, MRI magnetic resonance imaging, HbF fetal hemoglobin.