Professionals

NEDLAAD is the most common form of disorder associated with variants in CAPRIN1.
Clinical features: patients are characterized by language delay (100% of cases), intellectual or learning disabilities (83%), attention deficit hyperactivity disorder (82%), autism spectrum disorder (67%), developmental delay (42%) and seizures (33%). Additional features include non-specific facial dysmorphisms, respiratory issues, skeletal and ocular anomalies, hearing impairment and gastrointestinal issues.

Prevalence: To date, only 12 patients have been deeply described worldwide in the literature, making NEDLAAD an ultra-rare disorder. However, CAPRIN1 has only recently been added to most diagnostic genetic panels; therefore, this prevalence may be underestimated.

Inheritance:NEDLAAD is an autosomal dominant disorder, mainly caused by de novo variants in CAPRIN1 gene. An incomplete penetrance or variable expressivity is plausible, as cases with variants inherited from healthy or mildly affected parents have been described.

Molecular genetics: NEDLAAD is associated with loss-of-function variants in CAPRIN1. Indeed, nonsense and frameshift variants have been described, together with copy number variations (deletions) encompassing CAPRIN1 gene. It has been demonstrated that these variants cause the loss of expression of one allele of CAPRIN1, leading to a half-dose of protein levels. Splicing variants have also been reported, and a loss-of-function mechanism for some of them has been also described.

CONDCAD has been described in three patients, and detailed information are available for two of them.
Clinical features: Two out of two patients are characterized by cerebral and/or cerebellar atrophy, intellectual or learning disability, bulbar symptoms, trunk instability, ataxia, and muscle weakness/hypotrophy. In one out of two cases additional features have been reported: neurogenic fiber atrophy, sensorimotor axonal neuropathy, social impairment, cognitive decline, attention deficit, scoliosis, and gait anomalies.

Prevalence: Three cases worldwide have been described/reported.

Inheritance:CONDCAC is an autosomal dominant disorder, caused by de novo variants in CAPRIN1 gene.

Molecular genetics: CONDCAC is caused by the change of the amino acid Proline in position 512 to a Leucine. This change, likely cause a gain-of-function of CAPRIN1 protein, leading to an increased ability to form stress granules. The clear mechanism in a neuronal context has not bee described yet.