Unraveling the Genetics Behind Orofacial Clefts and Achromatopsia: Two Inspiring Studies Using Golden Helix Products

         March 30, 2023

Explore how Golden Helix products aid groundbreaking studies on orofacial clefts and achromatopsia, showcasing their versatility and enhancing our understanding of these rare conditions.

We are always humbled and thrilled to learn how Golden Helix products are being used in the arena of human genetic testing.  This month is no exception, as we showcase two very interesting studies.  In the first study, the investigators focused on the genetic etiology of OFCs.  Cleft lip with or without cleft palate, and cleft palate alone, are collectively referred to as orofacial clefts (OFCs).  OFCs are considered very rare in the US, with fewer than 20,000 cases per year.  However, OFCs are one of the most common congenital abnormalities, with causes including both Mendelian genetic causes as well as environmental causes.  The study included 31 families from the United States, Europe, Asia, and Central America.  Whole Exome Sequencing was used to find rare, likely causal genetic variants in the 31 OFC families.  Variants were filtered and annotated using VarSeq, from Golden Helix.  The author and investigators sought to test two complementary hypotheses.  Read further below to learn what they discovered!

The second study is a retrospective study of Danish patients investigating a rare congenital condition called Achromatopsia (ACHM). Also known as Rod monochromacy, Achromatopsia is a non-progressive and hereditary visual disorder characterized by a partial or total absence of color vision.  More men than women are affected, and there is no treatment for inherited color blindness.  The study describes the genetic background and phenotypical characteristics of Danish patients with ACHM.  Investigators sought to identify genetic variants believed to be disease-causing in known ACHM genes.  Genes associated with ACHM were included in a larger panel of genes associated with inherited retinal disease.  Among other methods, interpretation of the found variants was done using VarSeq from Golden Helix.  For the complete findings and results of the study, see the full article below. 

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

Whole-exome sequencing (WES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for WES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed whole-exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, KLF4, SHROOM3, SMC3, TP63, and TBX3 in seven families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs.

Genetic and Clinical Characterization of Danish Achromatopsia Patients

Achromatopsia is a rare congenital condition with cone photoreceptor dysfunction causing color blindness, reduced vision, nystagmus and photophobia. New treatments are being developed, but the current evidence is still conflicting regarding possible progression over time, and there is no clear genotype-phenotype correlation. This natural history study aimed to further explore the course of disease and potential clinical differences between various genotypes. The retrospective design allowed for the study of a large cohort with a long follow-up. Patients were identified from the Danish national registries. If not already available, genetic analysis was offered to the patient. Clinical data from 1945–2022 were retrieved from medical records and included best-corrected visual acuity (BCVA), color vision, refractive error, nystagmus, visual fields and fundoscopic findings. We identified variants believed to be disease causing in five of the known achromatopsia genes: CNGA3CNGB3GNAT2PDE6C and PDE6H; and novel variants were identified in CNGB3 and PDE6C. Progressive deterioration of BCVA only attributable to achromatopsia was found in three of 58 patients. Progressive phenotype was seen with variants in CNGB3 and PDE6C. The results indicate that myopia could be more frequently occurring with variants in GNAT2PDE6C and PDE6H and support the evidence that achromatopsia is a predominantly stationary condition with respect to BCVA. Although a clear genotype-phenotype correlation can still not be concluded, there may be differences in phenotypical characteristics with variants in different genes.

Are you intrigued by the power and versatility of VarSeq demonstrated in these groundbreaking studies? If so, it’s time to dive deeper and explore how VarSeq can revolutionize your genetic research efforts! VarSeq is an intuitive, user-friendly software designed to streamline your genomic data analysis, making it easier to filter, annotate, and interpret variants for both Mendelian and complex genetic disorders. Unleash the full potential of your genetic research with the help of VarSeq’s powerful features, customizable workflows, and seamless integration with other Golden Helix products. Don’t miss this opportunity to elevate your research capabilities – visit to learn more and start your journey with VarSeq today!

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