Front Cover: The cover image is based on the Research Article TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease by Weisheng Chen et al., https://doi.org/10.1002/humu.23907.

Cover image © Nan Wu Images.

Inside Back Cover: The cover image is based on the Research Article Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome by Hadia Hijazi et al., https://doi.org/10.1002/humu.23902.

Cover image © Hadia Hijazi & Ameerah Deyab Images.

Participation to external quality assessment (EQA) improved compliance with Human Genome Variation Society (HGVS) recommendations. Compliance of variant descriptions was better for next-generation sequencing (20.9%) compared with targeted techniques (9.8%). A correct reference sequence was included for 36.0% of noncommercial versus 26.5% of commercial test methods. The residual percentage of noncompliance with HGVS suggests that laboratories, companies, and EQA providers need to collaborate for additional harmonization in clinical test reporting.

Electron microscopy showing tubular aggregates in muscle fibers from a TAM/STRMK patient.

KCNB1 encodes the α subunit of the delayed rectifier voltage-dependent potassium channel K_v2.1. In this mutation update, we provide an up-to-date review of the mutational and clinical spectrum of the KCNB1 encephalopathy and report 18 novel variants.

CCDC39 mutations are a major cause for primary ciliary dyskinesia in Tunisia (44% of independent cases). One CCDC39 founder mutation, c.2190del, is found in 24% of patients. This ancestral allele is identified in other Mediterranean patients and it is estimated to have arisen at least 1,400 years ago.

Mucolipidosis (ML) II and III alpha/beta are inherited lysosomal storage disorders caused by mutations in GNPTAB encoding the α/β-precursor of GlcNAc-1-phosphotransferase. In this study, we report on four disease-associated, highly conserved amino acid residues in the so-called stealth domains of the GlcNAc-1-phosphotransferase, which are strictly required for enzymatic activity and thus may be directly involved in the enzymatic catalysis.

Gene dosage model of TBX6-associated congenital scoliosis (TACS). The phenotypes in TACS patients vary along with the dosage alterations of TBX6 expression.

In next-generation sequencing (NGS) hereditary cancer panel testing, TP53 pathogenic variants whose NGS allele frequencies might appear consistent with those expected for germline variants, but the variant might be acquired somatically. Confirming TP53 variant origin can markedly impact medical management for tested individuals and their family members. The report highlights the need for a conservative approach to initial reporting of TP53-positive findings, along with investment in follow-up testing to deliver clinically accurate results.

In this study, we report the confirmation of IQCE as a gene whose defects cause isolated postaxial polydactyly. Whole-exome sequencing has been applied to three families and revealed biallelic pathogenic variations in IQCE. Further functional analysis using the patient's cells (skin fibroblast) revealed no effect on the formation of the cilia but a mislocalization of the EVC2 and a defective hedgehog signaling. Zebrafish experiments demonstrated a full spectrum of phenotypes associated with defective cilia: Body curvature, kidney cysts, left–right asymmetry, misdirected cilia in the pronephric duct, and retinal defects.

MYH9-related disorder diagnosis is still challenging in clinical practice. We analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder and identified 50 patients with a rare variant in MYH9. In the presence of an unclassified platelet disorder with macrothrombocytes, MYH9-RD should always be considered.