BCL11A intellectual developmental disorder

Peron A, D'Arco F, Aldinger KA, Smith-Hicks C, Zweier C, Gradek GA, Bradbury K, Accogli A, Andersen EF, Au PYB, Battini R, Beleford D, Bird LM, Bouman A, Bruel AL, Busk ØL, Campeau PM, Capra V, Carlston C, Carmichael J, Chassevent A, Clayton-Smith J, Bamshad MJ, Earl DL, Faivre L, Philippe C, Ferreira P, Graul-Neumann L, Green MJ, Haffner D, Haldipur P, Hanna S, Houge G, Jones WD, Kraus C, Kristiansen BE, Lespinasse J, Low KJ, Lynch SA, Maia S, Mao R, Kalinauskiene R, Melver C, McDonald K, Montgomery T, Morleo M, Motter C, Openshaw AS, Palumbos JC, Parikh AS, Perilla-Young Y, Powell CM, Person R, Desai M, Piard J, Pfundt R, Scala M, Serey-Gaut M, Shears D, Slavotinek A, Suri M, Turner C, Tvrdik T, Weiss K, Wentzensen IM, Zollino M, Hsieh TC; C4RCD Research Group; Telethon Undiagnosed Disease Program (TUDP); University of Washington Center for Mendelian Genomics (UW-CMG); de Vries BBA, Guillemot F, Dobyns WB, Viskochil D, Dias C. BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations. Eur J Hum Genet. 2024 Oct 24. doi: 10.1038/s41431-024-01701-z. Epub ahead of print. PMID: 39448799.

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.

Peron A, Bradbury K, Viskochil DH, Dias C. BCL11A-Related Intellectual Disability. 2019 Sep 26. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 31556984.

Excerpt

Clinical characteristics: BCL11A-related intellectual disability (BCL11A-ID) is characterized by developmental delay / intellectual disability of variable degree, neonatal hypotonia, microcephaly, distinctive but variable facial characteristics, behavior problems, and asymptomatic persistence of fetal hemoglobin. Growth delay, seizures, and autism spectrum disorder have also been reported in some affected individuals.

Diagnosis/testing: The diagnosis of BCL11A-ID is established in a proband with suggestive clinical and laboratory findings and a heterozygous pathogenic variant in BCL11A identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment is primarily supportive and dictated by symptoms. Standard anti-seizure medication for seizure disorder; standard treatment for abnormal vision and/or strabismus, sleep disturbance, scoliosis, joint laxity, gastroesophageal reflux disease (GERD), constipation, and developmental issues.

Surveillance: Assessment of growth parameters, feeding difficulties, GERD, constipation, scoliosis, developmental progress, and behavior at each visit. Monitor seizures as clinically indicated. Assessment of vision and eye alignment as needed.

Genetic counseling: BCL11A-ID is inherited in an autosomal dominant manner; however, most affected individuals have the disorder as the result of a de novo BCL11A pathogenic variant. Once the BCL11A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.