MN1 Neurodevelopmental Disease-Atypical Phenotype Due to a Novel Frameshift Variant in the MN1 Gene

Background:MN1 C-terminal truncation (MCTT) syndrome is caused by variants in the C-terminal region of MN1, which were first described in 2020. The clinical features of MCTT syndrome includes severe neurodevelopmental and brain abnormalities. We reported on a patient who carried the MN1 variant in the C-terminal region with mild developmental delay and normal brain magnetic resonance image (MRI).Methods: Detailed clinical information was collected in the pedigree. Whole-exome sequencing (WES) accompanied with Sanger sequencing validation were performed. A functional study based on HEK239T cells was performed.Results: A de novo heterozygous c.3734delT: p.L1245fs variant was detected. HEK239T cells transinfected with the de novo variant showed decreased proliferation, enhanced apoptotic rate, and MN1 nuclear aggregation.Conclusion: Our study expended the clinical and genetic spectrum of MCTT which contributes to the genetic counseling of the MN1 gene.

Concurrent Onset of Chronic Lymphocytic Leukemia and Atypical Phenotype Acute Myeloid Leukemia Revealed by Autopsy

The concurrent onset of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) is rare, and no autopsy case has been reported. We report herein the first case of concurrent-onset CLL and AML with an atypical phenotype revealed by autopsy. Notably, the diagnosis of AML was quite difficult during the patient’s lifetime because of the atypical phenotype. However, autopsy revealed that the patient’s bone marrow, liver, and spleen were filled with myeloblasts. In addition, p53 stain and PCR of IgH rearrangement using the autopsy specimen suggested that CLL and AML might be different clones. In conclusion, our case highlights the importance of considering synchronous complications of AML in CLL patients, particularly in those with an atypical clinical course.

A de novo Variant of ASXL1 Is Associated With an Atypical Phenotype of Bohring-Opitz Syndrome: Case Report and Literature Review

Bohring-Opitz syndrome (BOS) is a rare genetic disease first reported by Bohring et al. in 1999. With the recent development of exome sequencing (ES), de novo truncating mutations in the additional sex-combs-like 1 (ASXL1) gene have been causally implicated in BOS. Herein, we describe a 7-month-old girl with intrauterine growth restriction, severe pulmonary infection, seizures, and craniofacial abnormalities (microcephaly, micro/retrognathia, hypertelorism, depressed nasal bridge, low-set ears and hypertrichosis) at birth. At a later stage, the patient developed global developmental delay. We performed ES and identified a de novo heterozygous mutation in ASXL1, namely, c.1210C>T/p.R404*. However, this case did not have trigonocephaly, facial hemangioma, prominent eyes, myopia, BOS posture, or brain abnormalities (enlarged subarachnoid spaces, agenesis of the corpus callosum, moderately enlarged cerebral ventricles, or prominent frontal subarachnoid spaces), which are common characteristics in most patients with BOS-harboring ASXL1 mutations. These new data expand the phenotype of BOS driven by ASXL1 and may assist in more accurately delineating the phenotypes caused by variants of this gene.

An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families

Diagnosis of myopathies is challenged by the high genetic heterogeneity and clinical overlap of the various etiologies. We previously reported a Next-Generation Sequencing strategy to identify genetic etiology in patients with undiagnosed Limb-Girdle Muscular Dystrophies, Congenital Myopathies, Congenital Muscular Dystrophies, Distal Myopathies, Myofibrillar Myopathies, and hyperCKemia or effort intolerance, using a large gene panel including genes classically associated with other entry diagnostic categories. In this study, we report the comprehensive clinical-biological strategy used to interpret NGS data in a cohort of 156 pediatric and adult patients, that included Copy Number Variants search, variants filtering and interpretation according to ACMG guidelines, segregation studies, deep phenotyping of patients and relatives, transcripts and protein studies, and multidisciplinary meetings. Genetic etiology was identified in 74 patients, a diagnostic yield (47.4%) similar to previous studies. We identified 18 patients (10%) with causative variants in different genes (ACTA1, RYR1, NEB, TTN, TRIP4, CACNA1S, FLNC, TNNT1, and PAPBN1) that resulted in milder and/or atypical phenotypes, with high intrafamilial variability in some cases. Mild phenotypes could mostly be explained by a less deleterious effect of variants on the protein. Detection of inter-individual variability and atypical phenotype-genotype associations is essential for precision medicine, patient care, and to progress in the understanding of the molecular mechanisms of myopathies.