1 - Serviço de Genética Médica, Hospital Dona Estefânia, Centro Hospitalar e Universitário de Lisboa Central, Lisboa, Portugal
2 - Unidade de Endocrinologia, Serviço de Pediatria Médica, Hospital Dona Estefânia, Centro Hospitalar e Universitário de Lisboa Central, Lisboa, Portugal
3 - Serviço de Pediatria, Hospital Distrital de Faro, Faro, Portugal
- ASHG Virtual Meeting, 18-22 de Outubro, virtual meeting. Sob a forma de poster.
Resumo:
Introduction: Haploinsufficiency of ARID1B gene disrupts the BAF complex, affects neural development, and it is one of the main causes of intellectual disability. Clinical evidence suggests that the spectrum of ARID1B-related disorders (ARID1B-RD) is highly variable and range from non-syndromic intellectual disability (ARID1B-ID) to CoffinSiris syndrome (ARID1B-CSS (#135900)). Typically, patients with ARID1B-CSS display hypertrichosis, sparse scalp hair, thick eyebrows, long eyelashes, thick alae nasi, long and broad philtrum, and aplasia or hypoplasia of the distal phalanx or nail of the fifth finger/toe. Other features present in ARID1B-RD include structural malformations (cardiac, central nervous system, musculoskeletal, gastrointestinal and genitourinary), laryngomalacia, feeding difficulties, growth problems, behavioural issues, and sensory impairment. Here, we present two cases that contribute to an increasing understanding of the clinical spectrum of ARID1B-RD.
Case report: One patient, a 8-year-old male, presented with intellectual disability, attention deficit hyperactivity disorder, facial dysmorphisms (posterior low hairline, low-set and posterior rotated ears, long eyelashes, thick eyebrows, abnormal nasal bridge, short nose), short stature, delayed bone age, laryngomalacia, pectus carinatum, pes planus, strabismus, and nystagmus. Exome sequencing identified a likely pathogenic variant in ARID1B (NM_001374820.1):c.1293_1320del p.(Ala432Metfs*11). Parent testing is ongoing. A second patient, a 3-year-old male, was referred for development delay, hypotonia, minor dysmorphisms (long eyelashes and full lips), deafness, laryngomalacia, food aversion, pyloric stenosis, umbilical hernia, recurrent infections, autistic traits, sleep disturbance and brain anomalies (midbrain and corpus callosum dysmorphisms). Exome sequencing identified a de novo pathogenic variant in ARID1B (NM_020732.3):c.5890G>T p.(Glu1964*).
Discussion: Both patients do not have a fully recognizable phenotype associated with ARID1B-CSS. Also, the overall phenotypes reflect the wide variability of ARID1BRD, and are consistent with the reported cases. To date, there is no established genotypephenotype correlation within the spectrum of ARID1B-RD and the severity of the phenotype.
Conclusions: With this work, we stress that ARID1B-RD spectrum is extremely wide and ARID1B-CSS is just the tip of the iceberg, as our patients highlight. We also bring to attention the importance of reverse phenotype when evaluating a patient with a neurodevelopment disorder and a pathogenic variant in ARID1B gene.
Palavras Chave: ARID1B-related disorders, chromatin, intellectual and developmental disability