Rajaa Fathallah

We identified a new progeroid syndrome with severe neuropathy and intellectual deficits but its underlying cellular and molecular mechanism is unknown. Exome sequencing revealed a homozygous mutation in the IVNS1ABP gene, which encodes IVNS1ABP, an influenza virus non-structural protein-1 binding protein. To investigate disease mechanisms, we generated isogenic induced pluripotent stem cells (iPSCs) from patient fibroblasts and differentiated them into neural progenitor cells (NPCs). Mutant IVNS1ABP fibroblasts, iPSCs, and NPCs exhibited defective cytokinesis, increased DNA damage, and premature cellular senescence. Consistent with these findings, cerebral organoids showed early differentiation of NPCs into neurons. Molecular profiling as well as biochemical and cellular analysis revealed altered binding of mutant IVNS1ABP to actin / actin-associated proteins and dysregulated actin dynamics during cytokinesis. Taken together, we propose that mutant IVNS1ABP dysregulates actin polymerization and organization which is at least partly responsible for the cellular senescence phenotypes in this progeroid neuropathy.

Spinal muscular atrophy (SMA) is a life-threatening, neuromuscular disease caused by variants in the survival motor neuron 1 (SMN1) gene, which affects spinal motor neurons resulting in progressive muscle weakness and hypotonia. This study aimed to identify the genetic diagnosis of SMA, present the outcomes of prenatal diagnosis, and provide an estimate for a minimum prevalence of the disease in Jordan. From 2007 through 2024, a total of 413 patients clinically suspected to have SMA and 243 at-risk prenatal cases were studied using diagnostic molecular testing. SMN1 exons 7 and 8 deletions were analyzed using either polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) (patients: n = 308, fetuses: n = 194) or multiplex ligation-dependent probe amplification (MLPA) (patients: n = 105, fetuses: n = 49). The copy number of SMN2 was determined for patients tested by MLPA. Homozygous deletion of SMN1 exon 7 was identified in 59.3% (245/413) of patients. Among them, 73.5% (n = 180) had SMA type I, 22.9% (n = 56) type II, and 3.7% (n = 9) type III. MLPA confirmed the diagnosis in 60% (63/105) of patients, with SMN2 copy numbers correlating with disease severity. A minimum prevalence of SMA was predicted to be 2.09 per 100,000 population with an incidence of 0.73 per 10,000 live births. Results on prenatal diagnostic cases showed 70.8% (172/243) of fetuses were unaffected. The study highlights the importance of SMA as a clinical health problem in Jordan and demonstrates MLPA as a reliable diagnostic tool. Our findings support the integration of SMA carrier screening into national newborn screening and premarital programs to enable early diagnosis, improve genetic counseling, and facilitate gene therapy options, ultimately improving overall patient outcomes and management.

Congenital anomalies are a heterogeneous disorder that occur during fetal development or infancy. Whole exome sequencing (WES) is a promising diagnostic tool for prenatal diagnosis. This study aimed to evaluate the efficiency of WES in identifying the genetic cause of fetal anomalies among Jordanian families. A total of 46 fetuses prenatally diagnosed with various congenital anomalies were included in this study. These cases were categorized into seven groups based on presented phenotypes. DNA was extracted from either chorionic villus samples or amniotic fluid and subjected to singleton WES to identify causative genetic variants. Clinical features and pregnancy outcomes were also collected and reviewed. Variant validation and segregation analysis were performed using ARMS-PCR or Sanger sequencing. Pathogenic or likely pathogenic variants were identified in 26/46 fetuses (56.5%) and variants of uncertain significance (VUS) were detected in 9/46 fetuses (19.6%). In total, 34 variants in 29 genes were identified including 13 pathogenic, 11 likely pathogenic, and 10 VUS. Twenty-three out of 34 variants have never been published. The identified variants were missense (n = 12, 35%), frameshift (n = 10, 29%), nonsense (n = 7, 21%), splice site (n = 3, 9%), and in-frame deletion (n = 2, 6%). Consanguinity was reported in 42 families (91.3%). This study underscores the value of WES in prenatal diagnosis and further expands the mutation spectrum associated with fetal anomalies. It also suggests that WES has strong potential to be used as a routine diagnostic tool in prenatal care. This method enables more precise genetic counseling and aids families facing a recurrent risk of fetal abnormalities in making informed reproductive decisions. To the best of our knowledge, this is the first study in Jordan to utilize prenatal WES for diagnosing fetal anomalies.