Differentiating molecular etiologies of Angelman syndrome through facial phenotyping using deep learning.

Angelman syndrome (AS) is caused by several genetic mechanisms that impair the expression of maternally-inherited UBE3A through deletions, paternal uniparental disomy (UPD), UBE3A pathogenic variants, or imprinting defects. Current methods of differentiating the etiology require molecular testing, which is sometimes difficult to obtain. Recently, computer-based facial analysis systems have been used to assist in identifying genetic conditions based on facial phenotypes. We sought to understand if the facial-recognition system DeepGestalt could find differences in phenotype between molecular subtypes of AS. Images and molecular data on 261 individuals with AS ranging from 10 months through 32 years were analyzed by DeepGestalt in a cross-validation model with receiver operating characteristic (ROC) curves generated. The area under the curve (AUC) of the ROC for each molecular subtype was compared and ranked from least to greatest differentiable phenotype. We determined that DeepGestalt demonstrated a high degree of discrimination between the deletion subtype and UPD or imprinting defects, and a lower degree of discrimination with the UBE3A pathogenic variants subtype. Our findings suggest that DeepGestalt can recognize subclinical differences in phenotype based on etiology and may provide decision support for testing.

Angelman Syndrome Caused by Chromosomal Rearrangements: A Case Report of 46,XX,+der(13)t(13;15)(q14.1;q12)mat,-15 with an Atypical Phenotype and Review of the Literature.

Less than 1% of the cases with Angelman syndrome (AS) are caused by chromosomal rearrangements. This category of AS is not well defined and may manifest atypical phenotypes. Here, we report a girl with AS due to der(13)t(13;15)(q14.1;q12)mat. SNP array detected the precise deletion/duplication points and the parental origin of the 15q deletion. Multicolor FISH confirmed a balanced translocation t(13;15)(q14.1;q12) in her mother. Her facial appearance showed some features of dup(13)(pter→q14). Also, she lacked the most characteristic and unique behavioral symptoms of AS, i.e., frequent laughter, happy demeanor, and easy excitability. A review of the literature indicated that AS cases caused by chromosomal rearrangements can be classified into 2 major categories and 4 groups. The first category is paternal uniparental disomy 15, which is subdivided into isodisomy by de novo rob(15;15) and heterodisomy caused by paternal translocation. The second category is the deletion of the AS locus due to maternal reciprocal translocation, which is subdivided into 2 groups associated with partial monosomy by 3:1 segregation and partial trisomy by adjacent-2 segregation. Classification into these categories facilitates the understanding of the mechanisms of chromosomal rearrangements and helps in accurate diagnosis and genetic counseling of these rare forms of AS.

Parent stress across molecular subtypes of children with Angelman syndrome.

BACKGROUND: Parenting stress has been consistently reported among parents of children with developmental disabilities. However, to date, no studies have investigated the impact of a molecular subtype of Angelman syndrome (AS) on parent stress, despite distinct phenotypic differences among subtypes. METHOD: Data for 124 families of children with three subtypes of AS: class I and II deletions (n = 99), imprinting centre defects (IC defects; n = 11) and paternal uniparental disomy (UPD; n = 14) were drawn from the AS Rare Diseases Clinical Research Network (RDCRN) database and collected from five research sites across the Unites States. The AS study at the RDCRN gathered health information to understand how the syndrome develops and how to treat it. Parents completed questionnaires on their perceived psychological stress, the severity of children's aberrant behaviour and children's sleep patterns. Children's adaptive functioning and developmental levels were clinically evaluated. RESULTS: Child-related stress reached clinical levels for 40% of parents of children with deletions, 100% for IC defects and 64.3% for UPD. Sleep difficulties were similar and elevated across subtypes. There were no differences between molecular subtypes for overall child and parent-related stress. However, results showed greater isolation and lack of perceived parenting skills for parents of children with UPD compared with deletions. Better overall cognition for children with deletions was significantly related to more child-related stress while their poorer adaptive functioning was associated with more child-related stress. For all three groups, the severity of children's inappropriate behaviour was positively related to different aspects of stress. CONCLUSIONS: How parents react to stress depends, in part, on children's AS molecular subtype. Despite falling under the larger umbrella term of AS, it is important to acknowledge the unique aspects associated with children's molecular subtype. Identifying these factors can lead to tailored interventions that fit the particular needs of families of children with different AS subtypes.

Longitudinal follow-up of autism spectrum features and sensory behaviors in Angelman syndrome by deletion class.

BACKGROUND: Angelman syndrome (AS) is a neurogenetic disorder characterized by severe intellectual disability, lack of speech, and low threshold for laughter; it is considered a 'syndromic' form of autism spectrum disorder (ASD). Previous studies have indicated overlap of ASD and AS, primarily in individuals with larger (∼6 Mb) Class I deletions of chromosome 15q11-13. Questions remain regarding whether intellectual disability solely contributes to ASD features in AS and how ASD features in AS change over time. In this study, we used a dimensional approach to examine ASD symptom severity in individuals with AS Class I versus Class II deletions within the context of cognitive development over time. METHODS: A total of 17 participants with a larger, Class I deletion and 25 participants with a smaller Class II deletion (∼5 Mb) were enrolled (age range = 2-25 years; 5 years 5 months). Standardized measures of cognition, language, motor skills, adaptive skills, maladaptive behavior, autism, and sensory-seeking behaviors/aversions were given at baseline and after 12 months. RESULTS: Despite equivalent cognition and adaptive behavior, the results of repeated measures analyses of variance indicate that participants with Class I deletions have greater impairment in social affect (F = 8.65; p = .006) and more repetitive behaviors (F = 7.92; p = .008) compared to participants with Class II deletions. Although both groups improve in cognition over time, differences in ASD behaviors persist. CONCLUSIONS: Despite a lack of differences in cognition or adaptive behavior, individuals with Class I deletions have greater severity in ASD features and sensory aversions that remain over time. There are four genes (NIPA 1, NIPA 2, CYFIP1, and GCP5) missing in Class I and present in Class Il deletions, one or more of which may have a role in modifying the severity of social affect impairment, and level of restricted/repetitive behaviors in AS. Our results also suggest the utility of a dimensional, longitudinal approach to the assessment of ASD features in populations of individuals who are low functioning.

Distinct phenotypes distinguish the molecular classes of Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a severe neurobehavioural disorder caused by defects in the maternally derived imprinted domain located on 15q11-q13. Most patients acquire AS by one of five mechanisms: (1) a large interstitial deletion of 15q11-q13; (2) paternal uniparental disomy (UPD) of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the E3 ubiquitin protein ligase gene (UBE3A); or (5) unidentified mechanism(s). All classical patients from these classes exhibit four cardinal features, including severe developmental delay and/or mental retardation, profound speech impairment, a movement and balance disorder, and AS specific behaviour typified by an easily excitable personality with an inappropriately happy affect. In addition, patients can display other characteristics, including microcephaly, hypopigmentation, and seizures. METHODS: We restricted the present study to 104 patients (93 families) with a classical AS phenotype. All of our patients were evaluated for 22 clinical variables including growth parameters, acquisition of motor skills, and history of seizures. In addition, molecular and cytogenetic analyses were used to assign a molecular class (I-V) to each patient for genotype-phenotype correlations. RESULTS: In our patient repository, 22% of our families had normal DNA methylation analyses along 15q11-q13. Of these, 44% of sporadic patients had mutations within UBE3A, the largest percentage found to date. Our data indicate that the five molecular classes can be divided into four phenotypic groups: deletions, UPD and ID patients, UBE3A mutation patients, and subjects with unknown aetiology. Deletion patients are the most severely affected, while UPD and ID patients are the least. Differences in body mass index, head circumference, and seizure activity are the most pronounced among the classes. CONCLUSIONS: Clinically, we were unable to distinguish between UPD and ID patients, suggesting that 15q11-q13 contains the only significant maternally expressed imprinted genes on chromosome 15.

Genetic counseling in Angelman syndrome: the challenges of multiple causes.

The causal heterogeneity of Angelman syndrome (AS) makes providing information regarding recurrence risk both important and challenging, and may have a dramatic impact on reproductive decision-making for the nuclear and extended family. Most cases of AS result from typical large de novo deletions of 15q11-q13, and are expected to have a low (<1%) risk of recurrence. AS due to paternal uniparental disomy (UPD), which occurs in the absence of a parental translocation, is likewise expected to have a <1% risk of recurrence. Parental transmission of a structurally or functionally unbalanced chromosome complement can lead to 15q11-q13 deletions or to UPD and will result in case-specific recurrence risks. In instances where there is no identifiable large deletion or UPD, the risk for recurrence may be as high as 50% as the result of either a maternally inherited imprinting center (IC) mutation or a ubiquitin-protein ligase (UBE3A) gene mutation. Individuals with AS who have none of the above abnormalities comprise a significant proportion of cases, and some may be at a 50% recurrence risk. Misdiagnoses, as well, can be represented in this group. In light of the many conditions which are clinically similar to AS, it is essential to address the possibility of diagnostic uncertainty and potential misdiagnosis prior to the provision of genetic counseling. Summaries of the different causal classes of AS as an algorithm for determination of recurrence risks are presented.