Accelerating the Development of Life-Changing Treatments for ARID1B-RD
ARID1B-related disorder (ARID1B-RD) is a rare genetic disorder that causes significant development delays and disabilities. Children and adults with ARID1B-RD typically have intellectual disability of variable degree, and may also have autistic features, seizures, delays or (near) absence of speech, as well as daily living and motor impairments. Most individuals with ARID1B-RD require continuous care throughout their lifespan and often struggle to live independently. Changes (variants) in the ARID1B (AT-Rich Interaction Domain 1B) gene are the most common cause of Coffin-Siris syndrome. At this point, there is no treatment for our loved ones, but the breathtaking advances in the application of novel clinical modalities give realistic hope that impactful treatments are within reach.
ARID1B is the most frequently mutated gene in NDDs that are not inherited, with an approximated prevalence of one in 9,500 individuals (1). This rate indicated that there could be up to 750,000 affected individuals across the world, and that every day 40 babies with ARID1B-RD are born. Currently, several hundreds of individuals have been diagnosed with ARID1B-RD.
The prevalence of ARID1B mutations in this population is estimated between 0.3 and 1 percent. ARID1B-RD affects every race and both genders. Still, the disorder is probably underdiagnosed because of its diverse manifestations and the lack of availability of genetic diagnostic testing (see diagnosis section below). Moreover, only a minority of children with autism spectrum disorder and other developmental delays are being referred to the required genetic testing.
Typical characteristics of ARID1B-RD are not usually evident at birth. Individuals with this disorder may have feeding difficulties as infants and noticeable delayed development around 6-12 months of age. The clinical manifestations of the disorder are broad and highly variable across individuals (i.e., not all individuals exhibit the same characteristics).
They often include mild to severe intellectual disability, delay or (near) absence of speech, delays in daily living and motor skills, and autism spectrum disorder features. Individuals affected by ARID1B-RD may have distinctive physical features, including coarse facial features, hypoplasia of the fifth digits and nails, sparse scalp hair, and hirsutism/hypertrichosis.
Common medical concerns include seizures, hypotonia, feeding difficulties (sometimes necessitate tube feeding), slow growth and scoliosis, laryngomalacia, cyroptorchism, and hearing and vision impairments. They need therapies to support the development of their functional skills and extensive medical attention. Notably, ARID1B-RD is non-progressive and tends to follow a relatively steady trajectory rather than a pattern of remitting and relapsing. However, data on adult patients is rather limited.
ARID1B is a central risk gene for ASD.
ARID1B is one of the most frequently mutated genes in intellectual disability.
Epilepsy occurs in up to 30% of children affected by ARID1B-RD.
ARID1B-RD is a single-gene disorder caused by a loss of function in the ARID1B gene on the 6th chromosome. Notably, people have two sets of chromosomes that include two copies of each gene. Among individuals with ARID1B-RD, only one copy of the ARID1B gene is not functional and the remaining functional copy is not enough to preserve normal function. This condition is termed haploinsufficiency and holds crucial clinical significance (see Research section).
Although ARID1B-RD is a genetic disorder, it is very rarely inherited. Instead, pathogenic (i.e., disease-causing) changes in the ARID1B gene occur as random events during the formation of reproductive cells or in early embryonic development. This kind of mutation is called de-novo.
Another clinically relevant note is that there are multiple known pathogenic variants in the ARID1B gene (i.e., deletion, frameshift, splice-site, nonsense, and missense).
Diagnosis of pathogenic mutations in the ARID1B gene requires genetic testing to identify abnormalities present in the gene level. Hence, a karyotype test, current noninvasive prenatal testing (NIPT), and simple chromosomal microarray analysis (CMA) cannot test for the presence of ARID1B mutations (though deletions may be identified in CMA).
Most ARID1B diagnoses are made using exome sequencing (sometimes called whole-exome sequencing [WES]; exome is the part of the genome that consists of DNA that codes for proteins). It should be noted that deletions in ARID1B can be missed depending on the type of analyses performed.
Importantly, ARID1B mutations can also be detected using multigene panels (a test that looks for mutations in a list of several genes often associated with specific observed conditions).