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This article reports on a case study of a newborn patient with trichothiodystrophy-3 (TTD3) caused by a novel homozygous variant in the GTF2H5 gene. The patient exhibited a severe phenotype, including congenital ichthyosis, complex cranial anomalies, life-threatening infections, and a complex cardiac malformation, which is unprecedented in TTD3 patients. Trichothiodystrophies are rare genetic disorders characterized by ichthyosis, skin photosensitivity, brittle hair, susceptibility to infections, intellectual impairment, short stature, and decreased fertility. The GTF2H5 gene is crucial for nucleotide excision repair activity and defects in this gene have been associated with TTD3. This case expands our understanding of the clinical and mutational landscape of GTF2H5 and highlights its potential for causing severe multisystemic damage. [Extracted from the article]

Polynucleotide kinase phosphatase (PNKP), encoded by the PNKP gene, is a DNA processing enzyme involved in double-strand break and single-strand break repair pathways, which are essential for genome stability and for the correct development and maintenance of human nervous system. PNKP biallelic loss-of-function variants have been associated with a broad spectrum of neurological anomalies, ranging from congenital microcephaly with intellectual disability and seizures (MCSZ), to later onset forms of ataxia-oculomotor apraxia (AOA4) or peripheral neuropathy (CMT2B2). We report the atypical clinical manifestations of a patient with severe microcephaly, short stature, developmental delay, conductive hearing loss, and tracheoesophageal malformation, in the absence of seizures. Whole exome sequencing analysis identified two novel, compound heterozygous splice-site variants in the PNKP gene (NM_007254.4): c.1448+1G > A and c.199-8_199-5del. To demonstrate the effect of both variants on the splicing process and prove their pathogenicity, we performed a hybrid minigene assay, which successfully highlighted a deleterious impact on the transcript, particularly regarding the c.199-8_199-5del variant. The uncommon clinical features of the proband and the identification of two newly associated pathogenic variants add further evidence to the allelic and phenotypic heterogeneity of the PNKP locus., (© 2024 The Author(s). American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)