Submission Details

SEC23B was first reported in relation to autosomal recessive congenital dyserythropoietic anemia II (CDANII) in 2009 (Bianchi et al. (PMID: 19621418) & Schwarz et al. (PMID:19561605)). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities: autosomal recessive CDAN2 (OMIM: 224100) & autosomal dominant Cowden Syndrome 7 (OMIM: 616858). A separate curation for Cowden Syndrome 7 was deemed not necessary by the Prenatal GCEP. 17 variants (missense, nonsense, splicing, frameshift) that have been reported in well over 20 probands probands in 4 publications (PMIDs: 19561605, 19621418, 27471141, 37373084) are included in this curation. Much more evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The prenatal phenotype includes fetal hydrops and anemia requiring transfusions before birth. The literature suggests that biallelic loss-of-function variants in SEC23B are incompatible with life. Neonatal jaundice and anemia are common in patients. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, expression-level evidence (PMIDs: 19561605, 34954140)). Expression-level data shows that SEC23B is expressed during differentiation of hematopoietic stem cells. The mouse model shows significant reduction in red blood cell count, hemoglobin levels, and hematocrit in the mutant mice compared to the wild-type. In summary, there is definitive evidence supporting the relationship between SEC23B and autosomal recessive CDANII. This been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Prenatal GCEP on the meeting date 10/2/2024 (SOP Version 10).