The OEIS complex – clinical & radiological evaluation

The OEIS complex comprises a constellation of complex and severe malformations of the abdominal wall, gastrointestinal and genitourinary tracts, and spinal cord. The malformation results from improper closure of the ventral abdominal wall due to failure of convergence of cephalo-caudal and lateral folding of the embryo during early gestation. The rarity of the condition suggests etiologic heterogeneity and the possible role of environmental and genetic factors. We present clinical and imaging findings of the OEIS complex in a neonate.

Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity

Variant prioritization of exome sequencing (ES) data for molecular diagnosis of sensorineural hearing loss (SNHL) with extreme etiologic heterogeneity poses a significant challenge. This study used an automated variant prioritization system (“EVIDENCE”) to analyze SNHL patient data and assess its diagnostic accuracy. We performed ES of 263 probands manifesting mild to moderate or higher degrees of SNHL. Candidate variants were classified according to the 2015 American College of Medical Genetics guidelines, and we compared the accuracy, call rates, and efficiency of variant prioritizations performed manually by humans or using EVIDENCE. In our in silico panel, 21 synthetic cases were successfully analyzed by EVIDENCE. In our cohort, the ES diagnostic yield for SNHL by manual analysis was 50.19% (132/263) and 50.95% (134/263) by EVIDENCE. EVIDENCE processed ES data 24-fold faster than humans, and the concordant call rate between humans and EVIDENCE was 97.72% (257/263). Additionally, EVIDENCE outperformed human accuracy, especially at discovering causative variants of rare syndromic deafness, whereas flexible interpretations that required predefined specific genotype–phenotype correlations were possible only by manual prioritization. The automated variant prioritization system remarkably facilitated the molecular diagnosis of hearing loss with high accuracy and efficiency, fostering the popularization of molecular genetic diagnosis of SNHL.

658Familial aggregation of melanoma by anatomic site of occurrence

Background Evidence is emerging that melanoma has distinct etiologic pathways and subtypes, characterized by factors like anatomic site. For example, older men have more head and neck melanomas, and younger women more leg melanomas. Family history is a strong risk factor and familial risk genes have been identified. We therefore aimed to investigate familial aggregation of melanoma from an etiologic heterogeneity perspective, to determine whether melanoma subtypes aggregate within families. Methods Using population-level linked health data, we examined the extent to which melanomas in first-degree relatives (FDRs) of cases shared the same body site of occurrence. FDR-pairs diagnosed with melanoma were identified using the Western Australian Cancer Registry and genealogical Family Connections System. Site was categorized as head/neck, trunk/arms, or legs. We identified 1,006 pairs of tumours from 677 family pairs and used Chi-Squared tests to evaluate familial aggregation by site. Degrees of etiologic heterogeneity of individual site-pairs were characterized by site concordance odds ratios. Results Familial aggregation by site was statistically significant (P = 0.01). However, only the site pairings of head/neck versus trunk/arms showed strong evidence of familial concordance (OR = 1.7, 95% CI 1.1-1.7). Trends were broadly similar in same-sex pairs. Conclusions Results show modest evidence of familial aggregation of melanoma by site, with overall evidence of aggregation but inconsistent patterns between sites. Key messages Strong etiologic differences in incidence between anatomic sites for age and sex may be more strongly influenced by non-genetic factors, such as familial patterns of sun exposure.

Validity of a method for identifying disease subtypes that are etiologically heterogeneous

A focus of cancer epidemiologic research has become the identification of risk factors that influence specific subtypes of disease, a phenomenon known as etiologic heterogeneity. In previous work we developed a novel strategy to cluster tumor markers and identify disease subtypes that differ maximally with respect to known risk factors for use in the context of case-control studies. The method relies on the premise that unsupervised k-means clustering will find candidate solutions that are closely aligned with the sought-after etiologically distinct clusters, which may not be true in the presence of clusters of tumor markers that are not related to risk of disease. In this article, we investigate in detail the ability of the method to identify the “true” clusters in the presence of clusters that are unrelated to risk factors, what we term “counterfeit” clusters. We find that our method works when the strength of structure is larger in the clusters that truly represent etiologic heterogeneity than in the counterfeit clusters, but when this condition is not met, or when there are many tumor markers that simply represent noise, the method will not find the correct solution without first performing variable selection to identify the tumor markers most strongly related to the risk factors. We illustrate the results using data from a breast cancer case-control study.

Fractionating autism based on neuroanatomical normative modeling

Autism is a complex neurodevelopmental condition with substantial phenotypic, biological, and etiologic heterogeneity. It remains a challenge to identify biomarkers to stratify autism into replicable cognitive or biological subtypes. Here, we aim to introduce a novel methodological framework for parsing neuroanatomical subtypes within a large cohort of individuals with autism. We used cortical thickness (CT) in a large and well-characterized sample of 316 participants with autism (88 female, age mean: 17.2 ± 5.7) and 206 with neurotypical development (79 female, age mean: 17.5 ± 6.1) aged 6–31 years across six sites from the EU-AIMS multi-center Longitudinal European Autism Project. Five biologically based putative subtypes were derived using normative modeling of CT and spectral clustering. Three of these clusters showed relatively widespread decreased CT and two showed relatively increased CT. These subtypes showed morphometric differences from one another, providing a potential explanation for inconsistent case–control findings in autism, and loaded differentially and more strongly onto symptoms and polygenic risk, indicating a dilution of clinical effects across heterogeneous cohorts. Our results provide an important step towards parsing the heterogeneous neurobiology of autism.

Parents of Children With Nonsyndromic Orofacial Clefting Show Altered Palate Shape

Objective: The unaffected relatives of individuals with nonsyndromic orofacial clefts have been shown to exhibit subtle craniofacial differences compared with the general population. Here, we investigate whether these morphological differences extend to the shape of the palate. Design: We conducted a geometric morphometric analysis to compare palate shape in the clinically unaffected parents of children with nonsyndromic cleft lip with or without cleft palate and adult controls of European, Asian, and African ancestry. We conducted pairwise group comparisons using canonical variates analysis, and then confirmed and characterized findings of shape differences using Euclidean distance matrix analysis. Results: Significant differences in palate shape were detected in unaffected mothers (but not fathers) compared to demographically matched controls. The differences in shape were ancestry-specific; mothers of Asian-derived and African-derived ancestry showed wider and shorter palates with higher posterior palatal vaults, while mothers of European-derived ancestry showed narrower palates with higher anterior palatal vaults. Conclusions: Our findings suggest that altered palate shape is a subclinical phenotypic feature, which may be indicative of elevated orofacial cleft risk. The risk phenotype varied by sex and ancestry, suggesting possible etiologic heterogeneity among demographic groups. Understanding the genetic basis of these informative palate shape traits may reveal new genes and pathways relevant to nonsyndromic orofacial clefting.

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors and likely gene–environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH. De novo variants are frequently associated with PAH in children and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, increased etiologic heterogeneity, poorer prognosis, and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

Assessment of mismatch repair protein expression by immunohistochemistry in endometrial carcinomas with clinicopathological correlation: A study from Indian Tertiary Cancer Care Centre

Objectives: Endometrial carcinomas (EC) are known to be histologically and biologically heterogeneous, and their recent molecular characterization has highlighted their etiologic heterogeneity. The aim of the present study was to analyze mutations in mismatch repair (MMR) proteins in ECs by immunohistochemistry (IHC), and correlates the data with their pathological parameters. Material and Methods: The expression of MMR proteins was analyzed using IHC in VENTANA BENCHMARK XT system, on formalin-fixed paraffin-embedded tumor tissue. The study population included 102 newly diagnosed cases of ECs over a duration of 2 years. Results: On histopathologic subtyping, 85.1% of cases were of Type 1 EC, 9.8% were Type 2 EC, and 4.9% were malignant mixed Mullerian tumors. On IHC for MMR protein expression, 22 of 102 cases (21.6%) showed loss of one or more protein, and mean age of patients with deficient MMR (dMMR) was 59.6 years. All of these dMMR cases were of endometrioid subtype, forming 25.3% of EEC. The combined loss of MLH1 and PMS2 was the most common abnormality detected (50% of dMMR). On pathological correlation, 54.5% of dMMR cases were found to be of higher grade (grade 2/3; P = 0.002) and 68.2% were higher stage tumors (T1b and above; P < 0.0001). The lymph-vascular invasion was seen in 50% of dMMR cases (4 of 8 cases). Conclusion: Detecting MMR protein loss in ECs by IHC is an efficient, relatively simple, and economical method. It needs to be routinely performed in all cases of ECs. Studies are still underway to utilize it as a therapeutic modality using immunotherapy.

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Pulmonary arterial hypertension is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors, and likely gene x environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to at least 36% of pediatric-onset idiopathic PAH (IPAH) compared to ~11% of adult-onset IPAH. De novo variants are frequently associated with PAH in children, and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, the increased etiologic heterogeneity, poorer prognosis and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.