Expanded carrier screening (ECS) has emerged as a cornerstone of reproductive genetics, enabling the identification of couples at risk of transmitting autosomal recessive and X-linked disorders. Advances in next-generation sequencing and the increasing adoption of exome- and genome-based strategies have greatly expanded its clinical scope. However, despite existing national and international recommendations, substantial heterogeneity remains in gene panel composition, inclusion criteria, and interpretation frameworks. A key novelty of the current genomic era is the availability of large, publicly accessible human genome datasets encompassing broader ancestral diversity. These resources are transforming our understanding of variant frequencies and disease penetrance across populations, supporting the development of evidence-based and ancestry-informed gene panels. In parallel, recent studies investigating the genetic contribution of pathogenic variants to euploid pregnancy losses are opening new perspectives for ECS. Incorporating genes associated with lethal conditions in utero may enhance the predictive power of screening and deepen our understanding of reproductive outcomes, while also demanding careful consideration of clinical validity and counseling implications. This mini-review synthesizes current evidence on ECS, examines ongoing interpretive and implementation challenges, and discusses how population-scale genomic resources and emerging data on reproductive lethality are shaping the next generation of evidence-based carrier screening.

Androgen insensitivity syndrome (AIS) is one of the most common Disorders of Sexual Differentiation (DSDs). AIS is characterized by an X-linked recessive inheritance pattern associated with variants in the androgen receptor (AR) gene that affects the masculinization process in individuals with XY karyotype. Here, we report a neonatal case of a very early diagnosis of complete AIS due to a novel variant in the AR gene. In the present case, after the clinical evaluation, the infant has undergone the following tests: biochemical analyses, including newborn screening workflow, karyotype analysis, and Next-Generation Sequencing (NGS) panel of 50 genes involved in DSDs. The NGS analysis identified a missense variant, c.2108C>A, in the AR gene. According to a cytogenetic analysis, the patient presented a 46, XY karyotype, thus the resulting hemizygote for the AR gene variant. The variant is not currently described in the literature nor in the ClinVar database. However, according to computational models, the variant could have a pathogenetic effect. This clinical case reveals a novel variant of the AR gene with a possible pathogenetic effect associated with AIS and highlights the importance of a multidisciplinary approach for the timely diagnosis and appropriate follow-up of the patient.

Background: Pycnodysostosis is a rare autosomal recessive skeletal disorder caused by biallelic pathogenic variants in CTSK, which encodes cathepsin K, a lysosomal cysteine protease required for osteoclast-mediated degradation of bone matrix. Case Report: We describe a girl with short stature, skeletal deformities, osteosclerosis, craniofacial features, clavicular dysplasia, and radiological evidence of fractures. Clinical exome sequencing identified two heterozygous CTSK variants, c.85T > C (p.Trp29Arg) and c.679A>T (p.Ile227Phe), both currently classified as variants of uncertain significance. Segregation analysis showed that the variants were inherited in trans. Computational modeling and in silico prediction tools supported a possible deleterious effect on cathepsin K structure or function. Serum cathepsin K was higher in the patient than in two age-matched controls; this result is reported as an exploratory observation only. Increased serum cathepsin K may reflect altered expression, secretion, clearance, or accumulation of dysfunctional protein, but cannot be interpreted as proof of compensatory upregulation. Conclusions: The patient’s clinical and radiographic features, the biallelic trans configuration of the CTSK variants, their rarity in population databases, and computational predictions support p.Trp29Arg and p.Ile227Phe as strong candidate disease-associated variants. Functional studies are required to confirm their effect on cathepsin K expression, maturation, and enzymatic activity.