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Phenotype of fetus and father with Stickler syndrome due to a COL2A1 variant. (a) 3rd trimester ultrasound showing femoral shortening and bowing; (b) 3rd trimester ultrasound showing pathological lower facial angle at 44 • corresponding to microretrognathia; (c) Affected father: short and stocky appearance; (d) Feet of affected father; (d) Feet of affected father: right 4th toe and left 4th and 5th toes are proximally implanted and the lower limbs show bowing at the ankles; (e) Left hand of affected father: short hand and brachydactyly.
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Whole exome sequencing (WES) has become part of the postnatal diagnostic work-up of both pediatric and adult patients with a range of disorders. In the last years, WES is slowly being implemented in the prenatal setting as well, although some hurdles remain, such as quantity and quality of input material, minimizing turn-around times, and ensuring...
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Context 1
... or likely pathogenic variants were identified in seven out of 28 (25%) cases: two de novo variants, four autosomal recessive and one paternally inherited (from an affected parent) (see Table 1). In three fetuses with skeletal anomalies, WES detected respectively a dominantly inherited COL2A1 variant (see Figure 3), a homozygous FANCG variant and a de novo KMT2D variant. The fetus with the COL2A1 variant displayed rhizomelic shortening and bowing of the long bones, microretrognathia and clenched hands-on prenatal ultrasound. ...
Context 2
... case of a suspicion of a fetal skeletal dysplasia, the value of adding WES to the prenatal diagnostic tools has been demonstrated before [20][21][22]; this was confirmed in our cohort, with three out of six cases (50%) being solved by WES. The fetus with Stickler syndrome type I (OMIM# 108300) caused by a heterozygous COL2A1 missense mutation (case 10) displayed rhizomelic shortening and bowing of the long bones as well as microretrognathia and clenched hands on ultrasound (Figure 3a,b). The mutation was paternally inherited, manifesting in the to that point undiagnosed father with severe myopia, hearing disorder, short stature, retrognathia, a nasal voice, tibia bowing, platyspondyly, coxofemoral dysplasia, hyperlordosis and rhizomelic shortening of the long bones (Figure 3c-e). ...
Context 3
... fetus with Stickler syndrome type I (OMIM# 108300) caused by a heterozygous COL2A1 missense mutation (case 10) displayed rhizomelic shortening and bowing of the long bones as well as microretrognathia and clenched hands on ultrasound (Figure 3a,b). The mutation was paternally inherited, manifesting in the to that point undiagnosed father with severe myopia, hearing disorder, short stature, retrognathia, a nasal voice, tibia bowing, platyspondyly, coxofemoral dysplasia, hyperlordosis and rhizomelic shortening of the long bones (Figure 3c-e). Analysis of the paternal grandparents demonstrated that the mutation arose de novo in the father. ...
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Citations
... In other cases, certain phenotypes, which are characteristic of particular genetic disorders such as epilepsy, cannot be assessed in utero while other features may only be detectable at specific developmental stages, usually later in pregnancy [6][7][8][9]. The lack of knowledge regarding prenatal phenotypic abnormalities in the literature also hinders the identification of disorders where the prenatal phenotype differs from the known neonatal clinical picture, which is often the case [7,10]. It is also important to note that phenotypic abnormalities can develop as well as resolve at different gestational stages; therefore, the monitoring of fetal structural abnormalities throughout pregnancy can be informative in regard to the associated genetic disorder [11]. ...
... In agreement with other studies, we highlight the importance of prenatal WES in fetuses with a normal karyotype and array-CGH result, especially in cases presenting skeletal and multisystem anomalies [8,10]. This study has contributed to enriching knowledge regarding the development of fetuses carrying variants in genes encoding VGSCs. ...
Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of action potentials in the brain and muscle. Pathogenic variants in genes encoding VGSCs have been associated with severe disorders including epileptic encephalopathies and congenital myopathies. In this study, we identified pathogenic variants in genes encoding the α subunit of VGSCs in the fetuses of two unrelated families with the use of trio-based whole exome sequencing, as part of a larger cohort study. Sanger sequencing was performed for variant confirmation as well as parental phasing. The fetus of the first family carried a known de novo heterozygous missense variant in the SCN2A gene (NM_001040143.2:c.751G>A p.(Val251Ile)) and presented intrauterine growth retardation, hand clenching and ventriculomegaly. Neonatally, the proband also exhibited refractory epilepsy, spasms and MRI abnormalities. The fetus of the second family was a compound heterozygote for two parentally inherited novel missense variants in the SCN4A gene (NM_000334.4:c.4340T>C, p.(Phe1447Ser), NM_000334.4:c.3798G>C, p.(Glu1266Asp)) and presented a severe prenatal phenotype including talipes, fetal hypokinesia, hypoplastic lungs, polyhydramnios, ear abnormalities and others. Both probands died soon after birth. In a subsequent pregnancy of the latter family, the fetus was also a compound heterozygote for the same parentally inherited variants. This pregnancy was terminated due to multiple ultrasound abnormalities similar to the first pregnancy. Our results suggest a potentially crucial role of the VGSC gene family in fetal development and early lethality.
... Recently another COL2A1 variant (p.Arg904Cys), with father-fetus transmission detected through trio-pES and associated to Stickler Syndrome type-1, has been reported with a more complex phenotype in the fetus, presenting additional and more severe findings in respect to the previously undiagnosed father (Janicki et al., 2023). ...
COL2A1 gene encodes the alpha-1 chain of type-II procollagen. Heterozygous pathogenic variants are associated with the broad clinical spectrum of genetic diseases known as type-II collagenopathies. We aimed to characterize the NM_001844.5:c.1330G>A;p.Gly444Ser variant detected in the COL2A1 gene through trio-based prenatal exome sequencing in a fetus presenting a severe skeletal phenotype at 31 Gestational Weeks and in his previously undisclosed mild-affected father. Functional studies on father's cutaneous fibroblasts, along with in silico protein modeling and in vitro chondrocytes differentiation, showed intracellular accumulation of collagen-II, its localization in external Golgi vesicles and nuclear morphological alterations. Extracellular matrix showed a disorganized fibronectin network. These results showed that p.Gly444Ser variant alters procollagen molecules processing and the assembly of mature type-II collagen fibrils, according to COL2A1-chain disorganization, displayed by protein modeling. Clinical assessment at 38 y.o., through a reverse-phenotyping approach, revealed limp gait, short and stocky appearance. X-Ray and MRI showed pelvis asymmetry with severe morpho-structural alterations of the femoral heads bilaterally, consistent with a mild form of type-II collagenopathy. This study shows how the fusion of genomics and clinical expertise can drive a diagnosis supported by cellular and bioinformatics studies to effectively establish variants pathogenicity.
... Further testing is needed to get a clearer picture of the prenatal diagnostic yield in the Romanian population. Genetic screening programs should be developed and implemented by the Department of Health together with healthcare professionals and a coordinating team should be assigned to evaluate and supervise these programs, to maintain and ensure their good use [29][30][31][32]. ...
Objective Our objective was to observe the benefits and limitations of WES (Whole Exome Sequencing) in the prenatal setting, in the Romanian population. The scope was to observe the diagnostic yield in comparison to molecular karyotyping testing, which had negative results, as well as a case of consanguinity. Methods The first criteria was selecting pregnancies with abnormal ultrasound findings. These findings would not lead the medical team to a certain known syndrome. Second, we performed SNP-array, which tested negative in all cases, except for Case number 9 which had an abnormal result. The ulterior testing method was WES, using Massive Parallel Sequencing of the whole coding region of the human genome on Next Generation Sequencing Platform, NovaSeq 6000 (average coverage >100X, read length: 2x100bp). The Twist Human Core Exome kit RefSeq & Mitochondrial panel (Twist Bioscience) was used for the library preparation. Bioinformatic analysis was performed by direct comparison of the genome of the test sample with the human reference sequence (hg38). Results Our small cohort of 10 patients, resulted in a 50% diagnostic yield. After receiving the results whether a diagnose or a negative result, 2 couples chose to terminate the pregnancy, 5 were born affirmatively without symptoms, and are still monitored up to date. One of the pregnancies led to a stillbirth. We have also found 3 incidental findings that helped the multidisciplinary team better manage the patient as well as the members at risk. Conclusion In this article we present 10 cases which were tested through prenatal WES, showing the great diagnostic yield in comparison to SNP-array in our selected cases. As a closing remark, we wish to highlight the benefits of WES testing in prenatal cases. Further testing is needed to get a clearer picture of the prenatal diagnostic yield in the Romanian population.
... These include 6305 phenotypes associated with one single gene, i.e., showing the monogenic nature of a genetic trait or syndrome. This was largely achieved due to the active implementation of WES and the exome consortium [28][29][30]. ...
Today, whole-exome sequencing (WES) is used to conduct the massive screening of structural and regulatory genes in order to identify the allele frequencies of disease-associated polymorphisms in various populations and thus detect pathogenic genetic changes (mutations or polymorphisms) conducive to malfunctional protein sequences. With its extensive capabilities, exome sequencing today allows both the diagnosis of monogenic diseases (MDs) and the examination of seemingly healthy populations to reveal a wide range of potential risks prior to disease manifestation (in the future, exome sequencing may outpace costly and less informative genome sequencing to become the first-line examination technique). This review establishes the human genetic passport as a new WES-based clinical concept for the identification of new candidate genes, gene variants, and molecular mechanisms in the diagnosis, prediction, and treatment of monogenic, oligogenic, and multifactorial diseases. Various diseases are addressed to demonstrate the extensive potential of WES and consider its advantages as well as disadvantages. Thus, WES can become a general test with a broad spectrum pf applications, including opportunistic screening.
Objective
This document addresses the clinical application of next-generation sequencing (NGS) technologies for prenatal genetic diagnosis and aims to establish clinical practice recommendations in Spain to ensure uniformity in implementing these technologies into prenatal care.
Methods
A joint committee of expert obstetricians and geneticists was created to review the existing literature on fetal NGS for genetic diagnosis and to make recommendations for Spanish healthcare professionals.
Results
This guideline summarises technical aspects of NGS technologies, clinical indications in prenatal setting, considerations regarding findings to be reported, genetic counselling considerations as well as data storage and protection policies.
Conclusions
This document provides updated recommendations for the use of NGS diagnostic tests in prenatal diagnosis. These recommendations should be periodically reviewed as our knowledge of the clinical utility of NGS technologies, applied during pregnancy, may advance.
