A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case

Costa, Claudia Ismania Samogy; Varella-Branco, Elisa; Monfardini, Frederico; Ferraz, Helen Conceição; Fock, Rodrigo Ambrósio; Barbosa, Ricardo Henrique Almeida; Pessoa, André Luiz Santos; Perez, Ana Beatriz Alvarez; Lourenço, Naila Cristina Vilaça; Vibranovski, Maria D.; Krepischi, Ana Cristina Victorino; Rosenberg, Carla; Passos‐Bueno, Maria Rita

doi:10.1186/s11689-019-9273-1

Cited by 42 publications

(67 citation statements)

References 25 publications

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“…100% of children were able to walk but at a delayed age, which is compatible with a different PMS cohort [32]. Lymphedema, hypothyroid, diabetes, vitiligo and enzyme deficiency absent in individuals in our cases have been reported in patients with PMS [5,22,23,27]. Furthermore, there was a remarkable difference in the frequency of certain PMS features (i.e.…”

Section: Discussionsupporting

confidence: 73%

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A 29 Mainland Chinese cohort of patients with Phelan–McDermid syndrome: genotype–phenotype correlations and the role of SHANK3 haploinsufficiency in the important phenotypes

Yang

et al. 2020

Orphanet J Rare Dis

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Background Phelan–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. Methods A 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. Results Nineteen 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. Conclusions This 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.

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Section: Discussionsupporting

confidence: 73%

“…Similarly, hearing loss reported in 3% of cases with PMS, were uncommon [27]. Lymphedema, hypothyroid, diabetes, vitiligo and enzyme deficiency have been reported in patients with PMS [5,22,23,27], but were absent in individuals in our cases (Table 3).…”

Section: Other Clinical Featuressupporting

confidence: 67%

A 29 Mainland Chinese cohort of patients with Phelan–McDermid syndrome: genotype–phenotype correlations and the role of SHANK3 haploinsufficiency in the important phenotypes

Yang

et al. 2020

Orphanet J Rare Dis

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“…A genotype-phenotype study of 71 patients showed an association between increased deletion size and 16 features [ 4 ]. Samogy-Costa et al found that renal abnormalities, lymphedema, and language impairment were positively associated with deletion sizes [ 5 ]. Moreover, 22q13.2q13.32 genomic regions were associated with the severity of speech delay, developmental delay, and physical features by statistical analysis in 70 patients with terminal 22q13 deletion [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…The SHANK3 gene has been identified as the critical candidate gene for the neurological features of this syndrome [2]. However, previous genotype-phenotype studies of PMS [3][4][5][6][7] and several case reports of 22q13 interstitial deletion [8][9][10] have implied the role of additional genes or regulatory regions proximal to the SHANK3 gene in PMS. Here, we report identical clinical and molecular findings from one pair of boy-girl twins with a de novo interstitial 22q13.31-q13.33 deletion not involving the SHANK3 gene.…”

Section: Introductionmentioning

confidence: 99%

Fraternal twins with Phelan-McDermid syndrome not involving the SHANK3 gene: case report and literature review

Liu

et al. 2020

BMC Med Genomics

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Background Phelan-McDermid syndrome (PMS, OMIM#606232), or 22q13 deletion syndrome, is a rare genetic disorder caused by deletion of the distal long arm of chromosome 22 with a variety of clinical features that display considerably heterogeneous degrees of severity. The SHANK3 gene is understood to be the critical gene for the neurological features of this syndrome. Case presentation We describe one pair of boy-girl twins with a 22q13 deletion not involving the SHANK3 gene. Interestingly, the clinical and molecular findings of the two patients were identical, likely resulting from germline mosaicism in a parent. The boy-girl twins showed intellectual disability, speech absence, facial dysmorphism, cyanosis, large fleshy hands and feet, dysplastic fingernails and abnormal behaviors, and third-generation sequencing showed an identical de novo interstitial deletion of 6.0 Mb in the 22q13.31-q13.33 region. Conclusions Our case suggests that prenatal diagnosis is essential for normal parents with affected children due to the theoretical possibility of parental germline mosaicism. Our results also indicated that other genes located in the 22q13 region may have a role in explaining symptoms in individuals with PMS. In particular, we propose that four candidate genes, CELSR1, ATXN10, FBLN1 and WNT7B, may also be involved in the etiology of the clinical features of PMS. However, more studies of smaller interstitial deletions with 22q13 are needed to corroborate our hypothesis and better define the genotype-phenotype correlation. Our findings contribute to a more comprehensive understanding of PMS.

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“…Although the prevalence of PMS is unknown, chromosome microarray and targeted resequencing of SHANK3 in ASD and ID suggest that up to 0.5–1% of subjects may show haploinsufficiency at this locus [5–8]. Because of its nonspecific clinical findings, the frequency of PMS is likely underestimated and is expected to increase with the widespread use of higher resolution microarrays and exome and genome sequencing with optimized coverage of SHANK3 [6, 7].…”

Section: Introductionmentioning

confidence: 99%

Neuropsychiatric decompensation in adolescents and adults with Phelan-McDermid syndrome: a systematic review of the literature

et al. 2019

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Phelan-McDermid syndrome (PMS) is caused by haploinsufficiency of the SHANK3 gene on chromosome 22q13.33 and is characterized by intellectual disability, hypotonia, severe speech impairments, and autism spectrum disorder. Emerging evidence indicates that there are changes over time in the phenotype observed in individuals with PMS, including severe neuropsychiatric symptoms and loss of skills occurring in adolescence and adulthood. To gain further insight into these phenomena and to better understand the long-term course of the disorder, we conducted a systematic literature review and identified 56 PMS cases showing signs of behavioral and neurologic decompensation in adolescence or adulthood (30 females, 25 males, 1 gender unknown). Clinical presentations included features of bipolar disorder, catatonia, psychosis, and loss of skills, occurring at a mean age of 20 years. There were no apparent sex differences in the rates of these disorders except for catatonia, which appeared to be more frequent in females (13 females, 3 males). Reports of individuals with point mutations in SHANK3 exhibiting neuropsychiatric decompensation and loss of skills demonstrate that loss of one copy of SHANK3 is sufficient to cause these manifestations. In the majority of cases, no apparent cause could be identified; in others, symptoms appeared after acute events, such as infections, prolonged or particularly intense seizures, or changes in the individual’s environment. Several individuals had a progressive neurological deterioration, including one with juvenile onset metachromatic leukodystrophy, a severe demyelinating disorder caused by recessive mutations in the ARSA gene in 22q13.33. These reports provide insights into treatment options that have proven helpful in some cases, and are reviewed herein. Our survey highlights how little is currently known about neuropsychiatric presentations and loss of skills in PMS and underscores the importance of studying the natural history in individuals with PMS, including both cross-sectional and long-term longitudinal analyses. Clearer delineation of these neuropsychiatric symptoms will contribute to their recognition and prompt management and will also help uncover the underlying biological mechanisms, potentially leading to improved interventions.

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A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case

Cited by 42 publications

References 25 publications

A 29 Mainland Chinese cohort of patients with Phelan–McDermid syndrome: genotype–phenotype correlations and the role of SHANK3 haploinsufficiency in the important phenotypes

A 29 Mainland Chinese cohort of patients with Phelan–McDermid syndrome: genotype–phenotype correlations and the role of SHANK3 haploinsufficiency in the important phenotypes

Fraternal twins with Phelan-McDermid syndrome not involving the SHANK3 gene: case report and literature review

Neuropsychiatric decompensation in adolescents and adults with Phelan-McDermid syndrome: a systematic review of the literature

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