A newly recognized multiple malformation syndrome with caudal regression associated with a biallelic c.402G>A variant in TBX4.

The T-box4 (TBX4) gene (OMIM *601719) belongs to the T-box family of transcription regulators that share a conserved homology domain and are expressed at specific sites during various stages of embryonic development. Tbx4 has been found to be a crucial transcriptional regulator in embryonic hindlimb development in animal models. Monoallelic variants in the TBX4 gene are reported to be associated with skeletal defects of the pelvis and lower limbs. We report here a fetus with a novel multiple malformation syndrome associated with sacrococcygeal agenesis, bilateral lower limb aplasia, hypoplastic left heart, bilateral lung hypoplasia, hydroureteronephrosis, and nonimmune fetal hydrops, found to have a homozygous nonsense variant in the TBX4 gene. We propose that biallelic variants in the TBX4 gene are associated with a severe syndromic phenotype of sacrococcygeal agenesis and lower limb reduction defects.

Molecular and Histopathological Characterization of Patients Presenting with the Duchenne Muscular Dystrophy Phenotype in a Tertiary Care Center in Southern India.

OBJECTIVE: To study the histopathological characteristics and mutation spectrum of patients presenting with the Duchenne muscular dystrophy (DMD) phenotype. METHODS: This was a descriptive study conducted over a period of 8 years. Multiplex ligation-dependent probe amplification (MLPA) was done in patients presenting with the DMD phenotype. If MLPA was negative, patients were offered muscle biopsy for histopathological studies and/or next generation sequencing (NGS) based multigene panel testing for muscular dystrophies. RESULTS: Of the 510 patients included, mutation in the DMD gene was detected by MLPA in 372 (72.9%), of whom 342 (67.1%) had exonic deletions and 30 (5.9%) had exonic duplications. Exons 45-55 were most commonly involved in large deletions and exons 1-10 were the commonest exons involved in duplications. In the MLPA-negative cohort, 27 proceeded for muscle biopsy. NGS was done in 14 patients, 10 of whom had pathogenic mutations in the DMD gene, 3 were non dystrophinopathies and no pathogenic variant could be identified in one patient. CONCLUSIONS: For patients presenting with the DMD phenotype, MLPA of the DMD gene has a high diagnostic rate of about 73%, and non-dystrophinopathies may constitute a small but significant proportion.