Publications by authors named "Tarfa Alshidi"
Background: Founder variants are ancestral variants shared by individuals who are not closely related. The large effect size of some of these variants in the context of Mendelian disorders offers numerous precision medicine opportunities.
Methods: Using one of the largest datasets on Mendelian disorders in the Middle East, we identified 2,908 medically relevant founder variants derived from 18,360 exomes and genomes and investigated their contribution to the clinical annotation of the human genome.
Article Synopsis
- Long-read whole genome sequencing (lrWGS) shows promise for diagnosing autosomal recessive diseases that exome sequencing fails to identify, as tested on a cohort of 34 families.
- In this study, likely causal variants were found in 13 families (38%), revealing novel candidate genes linked to conditions like neonatal lactic acidosis and neurodevelopmental disorders.
- The results indicate that while lrWGS can uncover complex genetic factors, there are still important interpretation challenges that need to be addressed to fully leverage this technology for genetic diagnosis.
Article Synopsis
- Many Mendelian disease patients still lack identified pathogenic variants despite extensive data-sharing efforts, signaling a need for better variant interpretation.
- *In a study of 4577 families, various challenges in identifying and interpreting novel variants were identified, including issues related to phenotype, pedigree structure, positional mapping, gene assertions, and complex inheritance patterns.
- *By tackling these non-sequencing challenges, researchers estimated a potential 71% increase in diagnostic success, achieving a 54.5% identification rate of causal variants in previously undiagnosed cases.*
Article Synopsis
- Colony-stimulating factor 3 (CSF3) is crucial for producing and functioning neutrophils and has been used in treatments for neutropenia for many years.
- Unlike the well-known issue with CSF3 receptor mutations causing severe congenital neutropenia (SCN), this study finds biallelic inactivating mutations in CSF3 itself linked to SCN in three patients from two families.
- The research shows that a complete lack of CSF3 was confirmed through analysis of RNA from skin cells, indicating that CSF3 deficiency leads to a new autosomal recessive type of SCN in humans, similar to findings in animal models.
SLC25A42 is the main transporter of coenzyme A (CoA) into mitochondria. To date, 15 individuals have been reported to have one of two bi-allelic homozygous missense variants in the as the cause of mitochondrial encephalomyopathy, of which 14 of them were of Saudi origin and share the same founder variant, c.871A > G:p.
View Article and Find Full Text PDFPurpose: Ciliopathies are highly heterogeneous clinical disorders of the primary cilium. We aim to characterize a large cohort of ciliopathies phenotypically and molecularly.
Methods: Detailed phenotypic and genomic analysis of patients with ciliopathies, and functional characterization of novel candidate genes.
Article Synopsis
- * A study identified a family with EK that shared similarities to mice deficient in the PERP gene, leading researchers to focus on a specific mutation in the PERP gene on chromosome 6.
- * Functional tests showed that the mutation negatively impacted PERP's role in skin cell organization, suggesting that EK can be inherited in an autosomal recessive manner due to the PERP mutation.
Mitochondrial calcium homeostasis is a tightly controlled process that is required for a variety of cellular functions. The mitochondrial calcium uniporter complex plays a critical role in this process. MICU2 is a major component of the mitochondrial calcium uniporter complex and its deficiency has been shown to impair mitochondrial calcium [Ca2+]m homeostasis although the exact mechanism remains unclear.
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- Variable expressivity occurs when individuals with the same gene mutation show different clinical symptoms, and this study explores the underlying mechanisms of this phenomenon.
- Four consanguineous families were studied, revealing that a new mutation in the 3' UTR of the SLC4A4 gene leads to an isolated eye condition rather than the expected multisystem disorder.
- The mutation creates a functional AU-rich element that reduces SLC4A4 mRNA stability by promoting decay, potentially explaining the varied clinical presentations associated with the gene.
PurposeThe application of genomic sequencing to investigate unexplained death during early human development, a form of lethality likely enriched for severe Mendelian disorders, has been limited.MethodsIn this study, we employed exome sequencing as a molecular autopsy tool in a cohort of 44 families with at least one death or lethal fetal malformation at any stage of in utero development. Where no DNA was available from the fetus, we performed molecular autopsy by proxy, i.
View Article and Find Full Text PDFLarsen syndrome is characterized by the dislocation of large joints and other less consistent clinical findings. Heterozygous FLNB mutations account for the majority of Larsen syndrome cases, but biallelic mutations in CHST3 and B4GALT7 have been more recently described, thus confirming the existence of recessive forms of the disease. In a multiplex consanguineous Saudi family affected by severe and recurrent large joint dislocation and severe myopia, we identified a homozygous truncating variant in GZF1 through a combined autozygome and exome approach.
View Article and Find Full Text PDFNonsense-mediated decay (NMD) is an important process that is best known for degrading transcripts that contain premature stop codons (PTCs) to mitigate their potentially harmful consequences, although its regulatory role encompasses other classes of transcripts as well. Despite the critical role of NMD at the cellular level, our knowledge about the consequences of deficiency of its components at the organismal level is largely limited to model organisms. In this study, we report two consanguineous families in which a similar pattern of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutations in SMG9, encoding an essential component of the SURF complex that generates phospho-UPF1, the single most important step in NMD.
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- Primordial dwarfism (PD) is a condition characterized by severe growth impairment before and after birth, resulting in very small adult size, and it's clinically diverse, with specific physical traits helping to categorize subtypes.
- The study introduces 16 new patients with PD, identifying a novel syndrome with unique facial features linked to distinct mutations in the CRIPT gene and discovering the first known case of a BRCA2 mutation causing PD.
- Additionally, researchers found a new gene associated with Seckel syndrome and brought attention to the gene XRCC4 as a potential contributor to PD, highlighting the complexity and genetic variability of the condition.
Orofaciodigital syndrome (OFD) is a recognized clinical entity with core defining features in the mouth, face, and digits, in addition to various other features that have been proposed to define distinct subtypes. The three genes linked to OFD-OFD1, TMEM216, and TCTN3-play a role in ciliary biology, a finding consistent with the clinical overlap between OFD and other ciliopathies. Most autosomal-recessive cases of OFD, however, remain undefined genetically.
View Article and Find Full Text PDFBackground: Genomic imbalances of the 12q telomere are rare; only a few patients having 12q24.31-q24.33 deletions were reported.
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