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Strong evidence for genotype-phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium.

ABSTRACT: Individuals with Phelan-McDermid syndrome (PMS) present with a wide range of developmental, medical, cognitive and behavioral abnormalities. Previous literature has begun to elucidate genotype-phenotype associations that may contribute to the wide spectrum of features. Here, we report results of genotype-phenotype associations in a cohort of 170 individuals with PMS. Genotypes were defined as Class I deletions (including SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B), Class II deletions (all other deletions) or sequence variants. Phenotype data were derived prospectively from direct evaluation, caregiver interview and questionnaires, and medical history. Analyses revealed individuals with Class I deletions or sequence variants had fewer delayed developmental milestones and higher cognitive ability compared to those with Class II deletions but had more skill regressions. Individuals with Class II deletions were more likely to have a variety of medical features, including renal abnormalities, spine abnormalities, and ataxic gait. Those with Class I deletions or sequence variants were more likely to have psychiatric diagnoses including bipolar disorder, depression, and schizophrenia. Autism spectrum disorder diagnoses did not differ between groups. This study represents the largest and most rigorous genotype-phenotype analysis in PMS to date and provides important information for considering clinical functioning, trajectories and comorbidities as a function of specific genetic alteration.

SUBMITTER: Levy T

PROVIDER: S-EPMC8863417 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Strong evidence for genotype-phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium.

Levy Tess T Foss-Feig Jennifer H JH Betancur Catalina C Siper Paige M PM Trelles-Thorne Maria Del Pilar MDP Halpern Danielle D Frank Yitzchak Y Lozano Reymundo R Layton Christina C Britvan Bari B Bernstein Jonathan A JA Buxbaum Joseph D JD Berry-Kravis Elizabeth E Powell Craig M CM Srivastava Siddharth S Sahin Mustafa M Soorya Latha L Thurm Audrey A Kolevzon Alexander A

Human molecular genetics 20220201 4

Individuals with Phelan-McDermid syndrome (PMS) present with a wide range of developmental, medical, cognitive and behavioral abnormalities. Previous literature has begun to elucidate genotype-phenotype associations that may contribute to the wide spectrum of features. Here, we report results of genotype-phenotype associations in a cohort of 170 individuals with PMS. Genotypes were defined as Class I deletions (including SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B), Class II deletions ...[more]

PMID: 34559195

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Project description:BackgroundPhelan-McDermid syndrome (PMS) is a neurodevelopmental disorder associated with a terminal deletion affecting chromosome 22 (22q13) that results in the loss of function of the SHANK3 gene. SHANK3 has also been identified in gene-linkage studies to be associated with autism spectrum disorder (ASD). Diagnosis of ASD in individuals with PMS is complicated by the presence of moderate to profound global developmental delay/intellectual disability as well as other co-morbid systemic and neurological symptoms.MethodsThe current study aimed to characterize the symptoms of ASD in patients with PMS and to do a preliminary exploration of genotype-ASD phenotype correlations. We conducted a standardized interview with 40 parents/guardians of children with PMS. Further, we conducted analyses on the relationship between disruption of SHANK3 and adjacent genes on specific characteristic symptoms of ASD in PMS in small subset of the sample.ResultsThe majority of PMS participants in our sample displayed persistent deficits in Social communication, but only half met diagnostic criteria under the restricted, repetitive patterns of behavior, interests, or activities domain. Furthermore, logistic regressions indicated that general developmental delay significantly contributed to the ASD diagnosis. The analyses relating the PMS genotype to the behavioral phenotype revealed additional complex relationships with contributions of genes in both deleted and preserved SHANK3 regions to the ASD phenotype and other neurobehavioral impairments.ConclusionsThere appears to be a unique behavioral phenotype associated with ASD in individuals with PMS. There also appears to be contributions of genes in both deleted and preserved SHANK3 regions to the ASD phenotype and other neurobehavioral impairments. Better characterization of the behavioral phenotype using additional standardized assessments and further analyses exploring the relationship between the PMS genotype and behavioral phenotype in a larger sample are warranted.

Project description:BackgroundPhelan-McDermid syndrome (PMS) or 22q13 deletion syndrome is a rare developmental disorder characterized by hypotonia, developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD) and dysmorphic features. Most cases are caused by 22q13 deletions encompassing many genes including SHANK3. Phenotype comparisons between patients with SHANK3 mutations (or deletions only disrupt SHANK3) and 22q13 deletions encompassing more than SHANK3 gene are lacking.MethodsA total of 29 Mainland China patients were clinically and genetically evaluated. Data were obtained from medical record review and a standardized medical history questionnaire, and dysmorphology evaluation was conducted via photographic evaluation. We analyzed 22q13 deletions and SHANK3 small mutations and performed genotype-phenotype analysis to determine whether neurological features and other important clinical features are responsible for haploinsufficiency of SHANK3.ResultsNineteen patients with 22q13.3 deletions ranging in size from 34 kb to 8.7 Mb, one patient with terminal deletions and duplications, and nine patients with SHANK3 mutations were included. All mutations would cause loss-of function effect and six novel heterozygous variants, c.3838_3839insGG, c.3088delC, c.3526G > T, c.3372dupC, c.3120delC and c.3942delC, were firstly reported. Besides, we demonstrated speech delay (100%), DD/ID (88%), ASD (80%), hypotonia (83%) and hyperactivity (83%) were prominent clinical features. Finally, 100% of cases with monogenic SHANK3 deletion had hypotonia and there was no significant difference between loss of SHANK3 alone and deletions encompassing more than SHANK3 gene in the prevalence of hypotonia, DD/ID, ASD, increased pain tolerance, gait abnormalities, impulsiveness, repetitive behaviors, regression and nonstop crying which were high in loss of SHANK3 alone group.ConclusionsThis is the first work describing a cohort of Mainland China patients broaden the clinical and molecular spectrum of PMS. Our findings support the effect of 22q13 deletions and SHANK3 point mutations on language impairment and several clinical manifestations, such as DD/ID. We also demonstrated SHANK3 haploinsufficiency was a major contributor to the neurological phenotypes of PMS and also responsible for other important phenotypes such as hypotonia, increased pain tolerance, impulsiveness, repetitive behaviors, regression and nonstop crying.

Project description:BackgroundPhelan-McDermid syndrome (PMS) is a rare genetic disorder compromising the 22q13 terminal region and affecting SHANK3, a gene crucial to the neurobehavioural phenotype and strongly linked to autism (ASD) and intellectual disability (ID). The condition is characterised by global developmental delay, ID, speech impairments, hypotonia and autistic behaviours, although its presentation and symptom severity vary widely. In this study, we provide a thorough description of the behavioural profile in PMS and explore differences related to deletion size and language ability.MethodsWe used standard clinical assessment instruments to measure altered behaviour, adaptive skills and autistic symptomatology in sixty participants with PMS (30 females, median age 8.5 years, SD=7.1). We recorded background information and other clinical manifestations and explored associations with deletion size. We performed descriptive and inferential analyses for group comparison.ResultsWe found delayed gross and fine motor development, delayed and impaired language (~70% of participants non or minimally verbal), ID of different degrees and adaptive functioning ranging from severe to borderline impairment. Approximately 40% of participants experienced developmental regression, and half of those regained skills. Autistic symptoms were frequent and variable in severity, with a median ADOS-2 CSS score of 6 for every domain. Sensory processing anomalies, hyperactivity, attentional problems and medical comorbidities were commonplace. The degree of language and motor development appeared to be associated with deletion size.ConclusionsThis study adds to previous research on the clinical descriptions of PMS and supports results suggesting wide variability of symptom severity and its association with deletion size. It makes the case for suitable psychotherapeutic and pharmacological approaches, for longitudinal studies to strengthen our understanding of possible clinical courses and for more precise genomic analysis.

Project description:BackgroundPhelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is characterized by global developmental delay, cognitive deficits, and behaviour in the autism spectrum. Knowledge about developmental and behavioural characteristics of this rare chromosomal disorder is still limited despite a rapid growing number of diagnoses. Our aim was to study a new and relatively large cohort to further characterize the developmental phenotype of children with PMS.MethodsWe performed a descriptive study of children with a 22q13.3 deletion including SHANK3, aged 8 to 178 months, who were systematically (n = 34) and longitudinally (n = 29) assessed with standardized instruments: Bayley Scales of Infant and Toddler Development, third edition; Wechsler Preschool and Primary Scale of Intelligence, third edition; and Vineland Screener for Social and Adaptive Behavior.ResultsMaximal developmental functioning ranged from 34 to 52 months depending on the developmental domain. In general, children performed poorest in the domain of language and best on the domain of motor (young children) or cognitive development (older children). At the individual level, 25 % scored better for receptive and 18 % for expressive language, whereas 22 % scored better for fine and 33 % for gross motor function. Developmental quotients were higher in younger children and decreased with age for all developmental domains, with 38 % of the children showing no improvement of cognitive developmental functioning. Almost all children (33/34) had significant deficits in adaptive behaviour. Children with very small deletions, covering only the SHANK3, ACR, and RABL2B genes, had a more favourable developmental phenotype.ConclusionsCognitive, motor, and especially language development were significantly impaired in all children with PMS but also highly variable and unpredictable. In addition, deficits in adaptive behaviour further hampered their cognitive development. Therefore, cognitive and behavioural characteristics should be evaluated and followed in each child with PMS to adapt supportive and therapeutic strategies to individual needs. Further research evaluating the relationship between deletion characteristics and the developmental phenotype is warranted to improve counselling of parents.

Project description:BackgroundPhelan-McDermid syndrome (PMS) is a rare genetic disorder characterized by global developmental delay, intellectual disability (ID), autism spectrum disorder (ASD), and mild dysmorphisms associated with several comorbidities caused by SHANK3 loss-of-function mutations. Although SHANK3 haploinsufficiency has been associated with the major neurological symptoms of PMS, it cannot explain the clinical variability seen among individuals. Our goals were to characterize a Brazilian cohort of PMS individuals, explore the genotype-phenotype correlation underlying this syndrome, and describe an atypical individual with mild phenotype.MethodologyA total of 34 PMS individuals were clinically and genetically evaluated. Data were obtained by a questionnaire answered by parents, and dysmorphic features were assessed via photographic evaluation. We analyzed 22q13.3 deletions and other potentially pathogenic copy number variants (CNVs) and also performed genotype-phenotype correlation analysis to determine whether comorbidities, speech status, and ASD correlate to deletion size. Finally, a Brazilian cohort of 829 ASD individuals and another independent cohort of 2297 ID individuals was used to determine the frequency of PMS in these disorders.ResultsOur data showed that 21% (6/29) of the PMS individuals presented an additional rare CNV, which may contribute to clinical variability in PMS. Increased pain tolerance (80%), hypotonia (85%), and sparse eyebrows (80%) were prominent clinical features. An atypical case diagnosed with PMS at 18 years old and IQ within the normal range is here described. Among Brazilian ASD or ID individuals referred to CNV analyses, the frequency of 22q13.3 deletion was 0.6% (5/829) and 0.61% (15/2297), respectively. Finally, renal abnormalities, lymphedema, and language impairment were found to be positively associated with deletion sizes, and the minimum deletion to cause these abnormalities is here suggested.ConclusionsThis is the first work describing a cohort of Brazilian individuals with PMS. Our results confirm the impact of 22q13 deletions on ASD and several comorbidities, such as hypotonia. The estimation of a minimal deletion size for developing lymphedema and renal problem can assist prediction of prognosis in PMS individuals, particularly those diagnosed in early infancy. We also identified one atypical individual carrying SHANK3 deletion, suggesting that resilience to such mutations occurs. This case expands the clinical spectrum of variability in PMS and opens perspectives to identify protective mechanisms that can minimize the severity of this condition.

Project description:IntroductionPhelan-McDermid syndrome (PMS) is a genetic disorder caused by the loss of the terminal region of chromosome 22 or by pathogenic or likely-pathogenic variants in SHANK3 gene. Individuals with PMS are affected by a variable degree of intellectual disability, delay or absence of speech, low muscle tone, motor delay epilepsy, and autistic features. We have performed an observational trial aimed to psychometrically characterize individuals carrying deletions or pathogenic variants in SHANK3, to eventually build a foundation for a subsequent precision psychiatry clinical trial with vafidemstat, a LSD1 inhibitor in Phase II clinical development.MethodsWe have conducted a pilot study to clinically characterize the profile of 30 subjects, all diagnosed of molecularly confirmed PMS. Subjects were phenotypically characterized by applying different psychometric scales, including Repetitive Behavior Questionnaire (RBQ), Vineland Adaptive Behavior Scales, ADOS-2, the Battelle developmental inventory screening test and the Behavior Problems Inventory (BPI). Nineteen patients were included in the pilot study, followed by additional 11 individuals in the validation set.ResultsUnsupervised hierarchical clustering of the collected psychometric data identifies three groups of patients, with different cognitive and behavioral profile scores. Statistically significant differences in deletion sizes were detected comparing the three clusters (corrected by gender), and the size of the deletion appears to be positively correlated with ADOS and negatively correlated with Vineland-A and -C scores. No correlation was detected between deletion size and the BPI and RBQ scores.DiscussionThis analysis presents new data on the best potential endpoints, for a future clinical study exploring vafidemstat actionability for SHANK3-associated psychiatric disorders, constituting a good example of how Precision Medicine may open new avenues to understand and treat Central Nervous System (CNS) disorders, pioneering individual management in PMS.

Dataset Information

Strong evidence for genotype-phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium.

Publications

Strong evidence for genotype-phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium.

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