This month we are thrilled once again to highlight two publications in which VarSeq plays an important role in the genetic testing pipeline. The continuing advances in Next Generation Sequencing (NGS) are assisting researchers and clinicians in gaining a deeper understanding of complex human syndromes, often referred to as congenital regulopathies. In this first study, genetic variants were discovered that contributed to developmental ocular anomalies. Specifically, investigators looked at heterozygous genetic variants identified in histone lysine methyltransferase (KMT) and demethylse (KDM) genes. There is growing evidence for the involvement of these genes in developmental ocular phenotypes, suggesting that further genetic testing in patients is important. In the study, the analysis of exome sequencing (detected variants) was done using VarSeq software (Golden Helix).
In the second study, investigators examined how better diagnostics may be achieved through genetic testing methods for Developmental dysplasia of the hip (DDH). DDH is a common musculoskeletal condition influenced by genetic, mechanical, and environmental factors, resulting in a wide range of phenotypic manifestations. The team stated that early detection of the condition contributes greatly to simpler and more effective treatments. All of the participants in the study were of Danish origin, belonging to a total of 29 families, and all were previously diagnosed with DDH. Whole Exome Sequencing was conducted to further understand the potential of a shared genetic cause of DDH in the study participants. Furthermore, VarSeq software (Golden Helix) was used for variant selection and annotation, done through a cascade of filtering steps. Finally, the study suggests that multiple genes contribute to the development of DDH and that predictive genetic testing may improve significantly diagnostic methods and patient management in families with a positive family history of DDH.
Distinct Roles of Histone Lysine Demethylases and Methyltransferases in Developmental Eye Disease
Members of the histone lysine methyltransferase and demethylase families function in opening and closing chromatin to control gene expression. Heterozygous truncating and loss-of-function missense variants in many members of these families have been associated with human disease, termed congenital regulopathies [1]. Variants in KMT2D and KDM6A result in Kabuki syndrome with dysmorphic facial features (long palpebral fissures, depressed nasal tip, and large ears), short stature, intellectual disability, hypotonia, skeletal anomalies including hip joint dislocation, abnormal finger pads, genitourinary malformation, immune deficiency, feeding disorders and congenital heart defects [2,3]. Kleefstra syndrome 2 is a rare condition caused by variants in KMT2C with moderate to severe cognitive impairment, autism, hypotonia, short stature and mild and variable dysmorphic facial features [4]. Variants in SETD1A (KMT2F) cause a neurodevelopmental phenotype with intellectual disability (typically mild), hypotonia, behavioral/psychiatric abnormalities, gastrointestinal anomalies, recurrent infections and dysmorphic craniofacial features including high forehead, ear anomalies and down-slanting palpebral fissures [5]. Claes-Jensen syndrome is an X-linked disorder caused by variants in KDM5C (JARID1C) which can affect both males and females with intellectual disability, seizures, short stature and craniofacial features; due to X-inactivation, only half of female carriers are affected [6,7]. Common features of these congenital regulopathies include cognitive impairment, craniofacial dysmorphism and short stature, underscoring the importance of histone regulation in the development of brain and craniofacial structures as well as prenatal/postnatal growth. The complex phenotypes associated with histone lysine methyltransferases and demethylases correspond with their broad effects on gene transcription and widespread expression, including in the developing ocular structures. Consistent with this expression pattern, we identified nine cases within our cohort of individuals with developmental ocular anomalies carrying genetic variants in KMT2D (five families) and four other histone lysine methyltransferases and demethylases (KMT2C, SETD1A (KMT2F), KDM6A and KDM5C), thus expanding the phenotypic spectra associated with these genes and suggesting distinct roles in human eye development.
Whole exome sequencing of 28 families of Danish descent reveals novel candidate genes and pathways in developmental dysplasia of the hip
Developmental dysplasia of the hip (DDH) is a common condition involving instability of the hip with multifactorial etiology. Early diagnosis and treatment are critical as undetected DDH is an important cause of long-term hip complications. Better diagnostics may be achieved through genetic methods, especially for patients with positive family history. Several candidate genes have been reported but the exact molecular etiology of the disease is yet unknown. In the present study, we performed whole exome sequencing of DDH patients from 28 families with at least two affected frst-degree relatives. Four genes previously not associated with DDH (METTL21B, DIS3L2, PPP6R2, and TM4SF19) were identifed with the same variants shared among affected family members, in more than two families. Among known association genes, we found damaging variants in DACH1, MYH10, NOTCH2, TBX4, EVC2, OTOG, and SHC3. Mutational burden analysis across the families identified 322 candidate genes, and enriched pathways include the extracellular matrix, cytoskeleton, ion-binding, and detection of mechanical stimulus. Taken altogether, our data suggest a polygenic mode of inheritance for DDH, and we propose that an impaired transduction of the mechanical stimulus is involved in the etiopathological mechanism. Our findings refine our current understanding of candidate causal genes in DDH, and provide a foundation for downstream functional studies.