Advancing the understanding of cognitive phenotypes in Shwachman Diamond syndrome through a diagnostic taxonomy: the International Classification of Cognitive Disorders in SDS (IC-CoD-SDS)

Purpose Shwachman Diamond syndrome (SDS) is a multisystemic autosomal recessive ribosomal disease (OMIM#260400) principally caused by biallelic variants in the SBDS gene. Although neuropsychological issues are prevalent, advancements in our understanding of associated cognitive phenotypes are impeded by the rarity of the disease and substantial heterogeneity patients’ neuropsychological test performance. An innovative classification framework using universal cognitive domains was recently developed to support international collaboration for harmonizing neuropsychological data to accelerate research into the neuropsychology of adults with epilepsy; namely, the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE). The current study leverages IC-CoDE to investigate its adaptability and feasibility for future collaborative international research in SDS, a crucial advance toward understanding the neuropsychology of this rare disease to enable more precise patient care. Methods Comprehensive neuropsychological data from 32 patients with SDS with biallelic SBDS causal variants (ages 6 to 16y) were available. We adapted the IC-CoDE model to address SDS-specific concerns by adding phonological awareness to the language domain and adding a social thinking domain. Using IC-CoDE guidelines we (1) applied impairment thresholds of − 1 and − 1.5 standard deviations (SD;16th and 5th percentiles) for each test for each individual; (3) determined cognitive domain impairment based on evidence from two or more tests within a domain; and (3) calculated the frequency and type of cognitive phenotypes based on the number of intact and impaired domains (single, bi-domain, generalized). Results Cognitive phenotypes using − 1 and − 1.5 SD thresholds showed intact profiles only in 1 and 9 patients (~ 3 and 28%), respectively. Single domain vulnerabilities were evident in 4 and 6 patients, bi-domain vulnerabilities in 5 and 7 patients, and generalized impairment in 20 and 10 patients (62.5 and 31.25%), respectively. Most notable were specific vulnerabilities evident in executive functioning followed by attention/processing speed, one or both of which were experienced in all patients with single, bi-domain and generalized impairment at both cutoffs. Conclusions Adapted from the IC-CoDE, the International Classification of Cognitive Disorders in SDS (IC-CoD-SDS) exhibits strong potential to address several existing barriers to understanding the neuropsychology of SDS, particularly the rarity of the disease. Notwithstanding the current sample size, the results accentuate the heterogeneity of cognitive performance and provide new and meaningful insights into the distinct phenotypes of SDS. This study demonstrates viability for utilizing IC-CoD-SDS to harmonize neuropsychological data held in SDS registries and in prospective studies. Implementation with larger international cohorts will be an essential advancement toward elucidating the nature, breadth, frequency and severity of cognitive vulnerabilities inherent in SDS and associated cognitive correlates (e.g., SDS genetics and neuroanatomical findings) to inform precision health.