Uniparental disomy (UPD) is a rare genetic event caused by errors during gametogenesis and fertilization leading to two copies of a chromosome or chromosomal region inherited from one parent. MixUPD is one type of UPD that contains isodisomic and heterodisomic parts because of meiotic recombination. Using whole-exome sequencing (WES), we identified the first case of ichthyosis due to a maternal mixUPD on chromosome 17, which results in a homozygous deletion of partial intron 8 to exon 10 in ALOX12B, being predicted to lead to an internal protein deletion of 97 amino acids. We also performed a retrospective analysis of 198 patients with ALOX12B mutations. The results suggested that the exon 9 and 10 are located in the mutational hotspots of ALOX12B. In addition, our patient has microtia and congenital stenosis of the external auditory canals, which is very rare in patients with ALOX12B mutations. Our study reports the first case of autosomal recessive congenital ichthyosis (ARCI) due to a mixUPD of chromosome 17 and expands the spectrum of clinical manifestations of ARCI caused by mutations in the ALOX12B gene.

Germline gain-of-function (GOF) mutations in the CARD11 gene lead to a rare primary immunodeficiency disease known as B cell expansion with NF-κB and T cell anergy (BENTA). Affected patients present with a polyclonal expansion of B cells, lymphadenopathy, and splenomegaly. Herein, we report a novel germline in-frame three base-pair deletion (c.1030_1032del, p.K344del) in the CARD11 gene in a patient with atypical BENTA, presenting with a recurrent fever and B cell lymphocytosis. This mutation was inherited from his mother, who is clinically asymptomatic and had a recurrent respiratory tract infection in her childhood. In vitro functional analysis demonstrated that this variant decreased the expression level of the CARD11 protein and activated the NF-κB signal pathway, leading to a higher expression of several NF-κB target gene transcripts in HCT116 cells transfected with mutant CARD11 (K344del-CARD11) as revealed by RNA sequencing analysis. To our knowledge, only 23 BENTA patients have been identified and carried seven distinct GOF mutations in CARD11. The clinical manifestations of patients are highly heterogeneous and there was no significant correlation between genotype and phenotype. In summary, we identified a novel in-frame three base-pair deletion that may be responsible for the pathogenesis of atypical BENTA in a Chinese family. Our study expands the mutational spectrum of the CARD11 gene and may be helpful in the understanding of diseases caused by CARD11 mutations and the clinical management of BENTA.

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Background Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of metabolic disorders caused by abnormal protein or lpid glycoproteins. DPM2 is a subunit of a heterotrimeric complex (dolichol-phosphate-mannose synthase, DPMS), a key enzyme in glycosylation, and only four patients with DPM2-CDG have been reported. Methods Whole exome sequencing (WES) was applied to analyze a Chinese family with two daughters with developmental delay, milder intellectual disability, hypotonia and increased serum creatine kinase. In vitro functional study was performed to evaluate the impact of pathogenic genetic mutation . Results A homozygous mutation, c.197G > A (p.G66E) in exon 4 of DPM2 gene (NM_003863) was identified by whole exome sequencing. In vitro functional analysis demonstrated that this variant increased the expression level of DPM2 protein and western blot revealed a significant decrease in ICAM1, a universal biomarker for hypoglycosylation in patients with CDG, suggesting abnormal N-linked glycosylation. We also review the 4 previously reported patients carried homozygous or compound heterozygous mutations of DMP2 gene, and found that mutations within the region encoding the first domain is correlated with more severe clinical symptoms than ones within the second domain, establishing the possible correlation of genotypes and phenotype based on the localization of the variants. Conclusions our study broadens the mutation spectrum of DPM2 genes, expands the genetic and phenotypic relevance of DPM2 variants, and emphasizes the need of further functional studies to understand the underlying pathophysiology of the phenotype heterogeneity.