We report the case of a Spanish female patient with progressive myopathy and severe muscle atrophy, intellectual delay, absence of expressive language development, overweight, and mitochondrial abnormalities. Whole-exome sequencing uncovered three heterozygous CHKB variants in the patient, one from the paternal allele and two from de maternal allele (NC_000022.11(NM_005198.5): c. [581G > A];[843 T > C;1031 + 3G > C]). This gene encodes the Choline/ethanolamine kinase (CHKB) protein, which catalyzes the first step of phosphatidylcholine biosynthesis. Pathogenic CHKB variants have been associated with megaconial congenital muscular dystrophy (MDCMC). In order to assess the pathogenicity of these variants, expression experiments of RNA for CHKB were carried out by RT-PCR from lymphocytes. The c.581G > A variant, instead to produce a missense change (p.Arg194Gln), induces an aberrant splicing event resulting in the deletion of exon 4 (V1 and V2: r.448_581del). On the other hand, the other two variants (c.843 T > C (p.Phe281 =) and c.1031 + 3G > C splice site variant) induces five alternative splicing events by altering the splice sites of exons 8 and 9 (V3: r.928_1031del, V4: r.970_1033del, V5: r.1026_1033del, V6: r.820_1032del and V7: r.819_927del). In all cases, the predicted codified proteins are truncated in carboxy-terminus, affecting to important domains of the protein or are likely to be degraded by NMD. In conclusion, we describe for the first time the pathological mechanism of the c.581G > A variant, show that c.843 T > C (synonymous variant) might be responsible for the exon 8 skipping, and confirm that c.1031 + 3G > C induces differential splicing as previously shown. Consequently, our findings provide additional functional evidences associated with CHKB variants.

Genodermatoses, a group of inherited skin disorders, are characterized by significant genetic heterogeneity and clinical variability, often posing diagnostic and therapeutic challenges. Advances in next-generation sequencing (NGS) technologies, such as whole exome sequencing (WES) and clinical exome sequencing (CES), have transformed the diagnostic landscape by enabling comprehensive genetic analysis. This study aimed to investigate the molecular spectrum and clinical relevance of genetic findings in 43 patients diagnosed with genodermatoses. Demographic, clinical, and molecular data were collected, and genetic testing was performed using the MGI-Seq platform. Variants were analyzed for pathogenicity, zygosity, and novelty. Neurofibromatosis Type 1 (27.9%) and Epidermolysis Bullosa (23.2%) were the most common diagnoses, followed by Ichthyosis (16.2%) and Oculocutaneous Albinism (13.9%). Less frequent conditions included Ectodermal Dysplasia (6.9%) and single cases of Palmoplantar Keratoderma, PTEN Hamartoma Syndrome, Rothmund-Thomson Syndrome, Xeroderma Pigmentosum, and Megaconial Congenital Muscular Dystrophy (each 2.3%). Molecular findings underscored the genetic complexity of genodermatoses, with 42 distinct variants identified across 19 genes. Of these, 13 variants (31%) were novel, expanding the known molecular spectrum. The novel variants were detected in genes including NF1, COL7A1, ITGB4, COL17A1, NIPAL4, ALOX12B, KRT10, ST14, OCA2, and PTEN, highlighting the diagnostic value of comprehensive genetic analysis. The mean age at diagnosis varied significantly among conditions, reflecting the diagnostic challenges and clinical variability of genodermatoses. This study emphasizes the critical role of WES and CES in diagnosing genodermatoses and understanding their molecular basis, which enhances diagnostic accuracy and supports personalized management strategies.

Megaconial congenital muscular dystrophy (MCMD) is a rare autosomal-recessive multisystem disorder characterized by delayed motor development, intellectual disability, and skin involvement. We report a patient with MCMD who had diffuse ichthyosis-like scaling, and successfully responded to ustekinumab.

The CHKB (choline kinase beta) gene plays a crucial role in regulating mitochondrial function and choline metabolism. Mutations in CHKB lead to conditions such as megaconial congenital muscular dystrophy (MCMD), characterized by enlarged mitochondria and impaired mitochondrial function, inducing various clinical features in neurological and cardiac performance. Herein, we report a rare case presenting with dilated cardiomyopathy as the dominant feature with a homozygous nonsense variant of CHKB, and the related therapeutic strategy. The proband, a 13-year-old male, presented with a complex clinical profile characterized by mild intellectual disability and severe cardiac impairment, including reduced activity tolerance, suspected acute heart failure, significant cardiac enlargement, a left anterior fascicular block, and a complete right bundle branch block. Whole exome sequencing (WES) identified a homozygous nonsense variant, c.598delC (p.Q200Rfs*11) of the CHKB gene, that resulted in disease caused by amino acid sequence changes, a truncated protein, and splice site changes, as demonstrated by MutationTaster analysis. The protein structure of CHKB was built and named AF-Q9Y259-F1. The residue around 200 amino acid sites changed in CHKB p.Q200Rfs*11 with unaltered hydrogen bonds which indicated the pathogenicity of the variant mainly originated from a truncated protein induced by the nonsense mutation. The heart blocks in the proband were considered to be associated with choline metabolic impairment, and thus cardiac resynchronization therapy would benefit the patient. Furthermore, the missense homozygous or compound heterozygous variants of CHKB, as well as the combined compound heterozygous missense and nonsense variants of CHKB, usually lead to neurological impairments and muscular weakness. This study expands the spectrum of CHKB mutations and provides essential information for the genotype-phenotype map of a nonsense variant of the gene. It is important to confirm a differential diagnosis among such patients using WES analyses. Regular cardiac and musculoskeletal monitoring is recommended for MCMD patients. Patients with a CHKB deficiency presenting with heart blocks could benefit from the administration of cardiac resynchronization therapy. This therapeutic approach might improve cardiac function and conduction in patients with CHKB-related cardiomyopathies.