Elucidating the genetic bases of selected rare disorders in consanguineous families

Rare diseases (RDs) are often severe clinical conditions that affect a much smaller percentage of the general population compared to other diseases. According to National Rare Diseases Registry System (NRDRS), 300 million people are significantly impacted by about 7000-10,000 rare disorders globally. Consanguineous marriages are strongly rooted social trend among 1/5th of the global population which allows the likelihood of transmitting mutated gene and imposed anticipated health risk to their offspring. In this study, Whole Exome Sequencing (WES) was performed to reveal the underlying genetic cause of three consanguineous families with rare genetic conditions. WES and subsequent segregation analysis identified 4 novel variants in three consanguineous Pakistani families segregating with 3 different types of autosomal recessive disorders. Various pathogenicity predicting tools were used to assess the pathogenicity of the identified variants. In family1, a novel homozygous missense variant (c. 1234 G>T) in BBS12 gene is considered as aplausible cause of Bardet Biedl Syndrome (BBS) phenotype however, another novel variant (c. 239 C>T) in USP53 gene is also segregating within pedigree. Bardet-Biedl syndrome (BBS) is an autosomal recessive rare genetic condition characterized by a heterogeneous clinical features, including rod-cone dystrophy, polydactyly, obesity, genital abnormalities, renal defects, and learning. 26 genes have been mapped till date for the disease that shows variable expressivity. A novel homozygous nonsense variant (c. 1201 C>U) in SACS gene associated with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay disease was identified in family 2. The disease is associated with progressive degeneration of the cerebellum and spinal cord. More than 300 variants have been discovered in the SACS gene around the world. A novel Missense variant (c. 729G>A) in GPT2 gene causing neurodevelopmental disorder with spastic paraplegia and microcephaly (NEDSPM) in family 3. NEDSPM is an autosomal recessive neurologic condition characterized by delayed psychomotor development, including delayed walking, moderately to severely impaired intellectual development, and poor or absent speech. Around 19 variants have been identified in GPT2 gene. The findings of current study not only expand the clinical and genetic spectra of identified genes but highlight the importance of next generation sequencing in heterogeneous rare disorders. Identification of disease-causing genetic variants will not only standardize the disease prevention by genetic counselling, cascade and prenatal screening but will provide better understanding of underlying disease mechanism and facilitate development of precise therapeutic interventions in future.

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