Background Due to inconsistencies with reported myofibrillar myopathy (MFM), including autosomal dominant inheritance, late onset and a slowly progressive course, the severe, recessively inherited form of CRYAB (alpha‐B crystallin) gene‐related infantile MFM has been suggested. Here, we report an infant in a Chinese family with fatal neonatal‐onset hypertonic MFM with a novel CRYAB homozygous variant (c.3G > A (p.Met1?)). Methods Muscle biopsy indicated that muscle fibers showed a uniformly small diameter, cell atrophy, and visible focal muscle fiber degeneration and necrosis consistent with myogenic myopathy. We performed the whole exome sequencing of pathogenic genes and identified it as MFM. Results The proband presented with profound muscle stiffness, progressive respiratory distress and a concurrent abnormal increase in myocardial enzymogram, and the patient died in the 17th month of life. Muscle biopsy and electron microscopy results were consistent with ultramicroscopic myogenic damage and pathological changes. Mutation analysis of the proband identified a novel rare homozygous mutation in the initiation codon of the CRYAB gene, which was inherited from currently asymptomatic, heterozygous carrier parents, and his heterozygous biological brother is unaffected. Conclusions This article reports one infant with CRYAB‐related neonatal onset MFM with a novel homozygous variant in CRYAB. To our knowledge, this is the first reported case of infantile alpha‐Bcrystallinopathy in the Chinese population.

Class III malocclusion is a common dentofacial deformity. The underlying genetic alteration is largely unclear. In this study, we sought to determine the genetic etiology for Class III malocclusion. A four‐generation pedigree of Class III malocclusion was recruited for exome sequencing analyses. The likely causative gene was verified via Sanger sequencing in an additional 90 unrelated sporadic Class III malocclusion patients. We identified a rare heterozygous variant in endoplasmic reticulum lectin 1 (ERLEC1; NM_015701.4(ERLEC1_v001):c.1237C>T, p.(His413Tyr), designated as ERLEC1‐m in this article) that cosegregated with the deformity in pedigree members and three additional rare missense heterozygous variants (c.419C>G, p.(Thr140Ser), c.419C>T, p.(Thr140Ile), and c.1448A>G, p.(Asn483Ser)) in 3 of 90 unrelated sporadic subjects. Our results showed that ERLEC1 is highly expressed in mouse jaw osteoblasts and inhibits osteoblast proliferation. ERLEC1‐m significantly enhanced this inhibitory effect of osteoblast proliferation. Our results also showed that the proper level of ERLEC1 expression is crucial for proper osteogenic differentiation. The ERLEC1 variant identified in this study is likely a causal mutation of Class III malocclusion. Our study reveals the genetic basis of Class III malocclusion and provides insights into the novel target for clinical management of Class III malocclusion, in addition to orthodontic treatment and orthodontic surgery.

BackgroundThe APLAID syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the PLCG2 gene. We present a 7-year-old APLAID patient who has recurrent blistering skin lesions, skin infections in the perineum, a rectal perineal fistula, and inflammatory bowel disease.MethodsTo determine the genetic cause of our patient, WES and bioinformatics analysis were performed. Flow cytometry was used for phenotyping immune cell populations in peripheral blood. Cytokines released into plasma were analyzed using protein chip technology. The PBMCs of patient and a healthy child were subjected to single-cell RNA-sequencing analysis.ResultsThe patient carried a novel de novo missense mutation c.2534T>C in exon 24 of the PLCG2 gene that causes a leucine to serine amino acid substitution (p.Leu845Ser). Bioinformatics analysis revealed that this mutation had a negative impact on the structure of the PLCγ2 protein, which is highly conserved in many other species. Immunophenotyping by flow cytometry revealed that in addition to the typical decrease in circulating memory B cells, the levels of myeloid dendritic cells (mDCs) in the children’s peripheral blood were significantly lower, as were the CD4+ effector T cells induced by their activation. Single-cell sequencing revealed that the proportion of different types of cells in the peripheral blood of the APLAID patient changed.ConclusionsWe present the first case of APLAID with severely reduced myeloid dendritic cells carrying a novel PLCG2 mutation, and conducted a comprehensive analysis of immunological features in the ALPAID patient, which has not been mentioned in previous reports. This study expands the spectrum of APLAID-associated immunophenotype and genotype. The detailed immune analyses in this patient may provide a basis for the development of targeted therapies for this severe autoinflammatory disease.

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