FEATURED Book Chapter Detail

From Monogenic Myths to Multigene Facts: Exploring Variable Inheritance and the Emergence of Digenic/Oligogenic Models in Human Diseases

Haseeba Shahzad^{1 ⃰}, Fizza Mubashir², Saba Irshad^{1 ⃰}, Muhammad Faheem Naeem³, Shah Hussain⁴, Sana Gulzar², Laraib Rana⁵, Amna Akram⁶, Busra Gunay⁷, Humaira Fayyaz⁸, Amer Shoaib⁸, Khadija Muzaffar¹, Maha Atif¹, Aqsa Nawaz⁹, Ayesha Liaqat¹⁰, Raafia Karamat¹, Saba Saeed⁹

¹School of Biochemistry and Biotechnology, University of the Punjab, Quaid-i-Azam Campus, Lahore, Pakistan

²Center of Excellence in Molecular Biology (CEMB), University of Punjab, Lahore, Pakistan

³Nishtar Medical University, Multan, Pakistan

⁴School of Pharmacy & Medical Sciences, Griffith University, Australia

⁵Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University,

Islamabad, Pakistan

⁶Faisalabad Medical University, Faisalabad

⁷Faculty of Science, Department of Biology, Ege University, Bornova, Izmir, Turkiye

⁸Fatima Memorial College of Medicine & Dentistry, Shadman, Lahore, Pakistan

⁹Department of Biochemistry, Bahauddin Zakariya University, Multan, Pakistan

¹⁰School of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, Lahore, Pakistan

*For Correspondence

haseeba.res.sbb@pu.edu.pk

saba.sbb@pu.edu.pk

The conventional "one gene–one disease" template has shaped our understanding of human genetics. Still, cumulative evidence reveals that this approach is too simplistic for verifying the entire spectrum of clinical phenotypes. It has been examined that presumed monogenic disorders often exhibit variable expressivity, incomplete penetrance, and inexplicable diagnostic gaps, the challenges that accentuate the impact of modifiers, genetic background, and additional molecular contributors. Therefore, modern genomics has switched towards multi-gene models, underscoring the mechanistic underpinnings of digenic/oligogenic inheritance. These patterns reveal the interplay of interacting proteins, pathways, polygenic load, and buffering capacity that collaboratively determine disease onset and severity. This switching clinically redefines genetic counseling, diagnostic strategies, and the ethical outlook of genomic medicine, requiring consolidation of progressive functional and bioinformatic interpretation tools. With the evolution of precision medicine, the embracement of genetic complexity is not only a scientific necessity but a clinical imperative. Shortly, the omics era is one of nuanced gene–gene interactions, interconnected networks, and redefined therapeutic horizons.

Keywords

Mendelian Concept, Monogenic Myths, Multigene Disorders, Variable Inheritance, Digenic/Oligogenic Models, Human Diseases