Background
Phelan-McDermid syndrome (PMS) [OMIM: 606232] is a rare genetic disorder compromising the 22q13 terminal region and affecting the SHANK3 gene. It is a neurodevelopmental disorder characterized by a large variety of clinical features with considerable heterogeneity in disease severity [1]. Clinically, affected patients present neonatal hypotonia, global developmental delay, absent speech, and moderate to profound intellectual disability (ID). The SHANK3 gene is a gene candidate for PMS, localized in the PMD region, as a result of an intragenic deletion or point mutation.
Described for the first time in 1958, PMS is now considered a relatively common cause of autism spectrum disorder (ASD) and ID. It is one of the most common sub telomeric deletions after 1p36.3 deletion syndrome. Indeed, it accounts for 1% of all ASD cases [2].
More than 1,200 cases have been reported worldwide and the prevalence is between 1/10,000 and 1/20,000 newborns. The deletion occurs with similar frequency in males and females [3]. However, PMS seems to be underdiagnosed, and its exact prevalence is still unknown [4]. To the best of our knowledge, no studies have been conducted on the Moroccan population [5].
Herein, we will present the clinical and genetic features of three patients with suspected PMS syndrome.
Cases Presentation
Cases 1 and 2: Five and 6-year-old Moroccan boys born from nonconsanguineous parents by normal delivery with a generalized neonatal hypotonia. The patients presented with delayed psychomotor development, absence of speech, autistic features, and common dysmorphic features. The first case presents lumbar depression, occult spina bifida, and bilateral flat feet. The second case presents a single palmar crease, a valgus foot, pylo-urethral junction, and right renal atrophy with dilatation of the excretory cavities and significant cortical atrophy with unremarkable medical history. There was no family history of a similar case.
Both cases have a normal constitutional karyotype (46, XY). However, the CGHarray testing showed a 3.2 Mb deletion in chromosome 22 (arr[GRCh37]22q13.31q13.33(47962298_51197766)x1). This deletion includes 50 genes including, the SHANK3 gene.
Case 3: A 19-year-old Moroccan female born to nonconsanguineous parents by normal delivery with a generalized neonatal hypotonia. The patient presented with ID, absence of language, and facial dysmorphia. The investigation of the family did not demonstrate any similar case. The standard constitutional karyotype was normal (46, XX). The chromosomal microarray analysis detected a microdeletion of 1.543 Mb in the region 22q13.33: arr[GRCh37] 22q13.33(49654561_51197838)x1. This deletion includes 42 genes, including the SHANK3 gene.
Discussion
PMD syndrome is a rare genetic disorder. Only a few mechanisms of this disease have been reported. Most of them consist of terminal chromosome 22q13 deletions that usually occur de novo, but in about 20% of cases, one parent carries a balanced translocation, intragenic SHANK3 deletions, or unbalanced translocations. Other chromosomal rearrangements lead to the formation of a ring chromosome 22, or disruptive point mutations in the SHANK3 gene [6].
The microdeletion identified in the 22q13.3 regions is the main cause of this syndrome. It is a recurrent and pathogenic copy number variant (CNV) susceptible to inducing neurodevelopmental disorders and absent or severely delayed expressive speech. The chromosomal deletion can reach several genes, including the SHANK3 gene, which contributes to the large interindividual phenotypic variability. Moreover, deletion sizes vary considerably among PMS patients, ranging from intragenic deletions of 100 Kb to around 9 Mb [4,5].
The karyotype should be the first genetic test to detect a rearrangement or a ring chromosome followed by a CGH array or FISH, because of the presence of large CNVs that cannot be identified by sequencing. Finally, a multigene panel including SHANK3 and other genes of interest has been developed to detect a heterozygous pathogenic variant [7].
The prevalence of PMD syndrome is still unknown. More than 1,500 individuals have been registered in the Foundation of PMS (Venice, Florida, 2017) [7]. Most of the patients included in the previous genotype-phenotype analyses carried microdeletions [8]. Indeed, the proportion of patients with SHANK3 variants is about 3%-25% (ClinVar, Varsome, LOVD databases), or 8.6% according to the PMS International Registry.
The Genotype-phenotype correlation in PMS is complex. Many studies have shown a relationship between deletion size and severity of features. Undeniably, the penetrance of the nonmosaic 22q13.3 deletion, including SHANK3 gene deletion is complete. However, small deletions non including SHANK3 are associated with non-penetrance and variable expressivity. Pathogenic variants in SHANK3 have been associated with PMS, nonsyndromic autism, and schizophrenia [7].
The haploinsufficiency of SHANK3, relates to many features, but most neurological and behavioral symptoms are also present in patients carrying interstitial 22q13 deletions without SHANK3 deletion [9]. This suggests thatthisgene maynot be responsible for the entire clinical spectrum of PMS [4]. A new classification of this disorder has been defined, comprising two categories: PMS-SHANK3 related for cases with deletions or pathogenic variants affecting SHANK3, and PMS-SHANK3 unrelated for the remaining cases where SHANK3 is preserved [6].
Individuals with the same size deletion may be vastly different in their degree of disability. Different factors are related, in the first the deletion sizes, and second, the environmental factors [5]. In the third, presence of variants in the remaining copy.
The prevalence of different features of Phelan-McDermid syndrome reported in the literature in comparison with that report in our case is represented in Table 1.
The PMS is caused by a deletion or a mutation of the SHANK3 gene with an autosomal dominant inheritance. Pathogenic variants in SHANK3 are usually de novo [7]. However, the terminal deletion could be inherited from an affected parent, which is very rare, and only one case has been described in the literature [10].
For all patients, a genetic investigation is needed to conduct full genetic counseling. In the present case, genetic screening of the parents could not be done because of lack of resources.
| Features | Prevalencea | our study |
|---|---|---|
| Neonatal hypotonia | 75% | 3/3 |
| Developmental delay | 75% | 3/3 |
| Absent or severely delayed speech | 75% | 3/3 |
| Normal growth | 75% | 3/3 |
| Decreased perception of pain | 75% | 3/3 |
| Mouthing /chewing/tooth grinding | 75% | 3/3 |
| Autism/autistic-like behavior | 75% | 3/3 |
| Dolichocephaly | 25% | 1/3 |
| Full or puffy eyelids | 50% | 3/3 |
| Strabismus | 25% | 1/3 |
| Full brow | 50% | 3/3 |
| Epicanthal folds | 25% | 3/3 |
| Long eyelashes | 50% | 2/3 |
| Prominent or large ears | 50% | 3/3 |
| Flat midface | 50% | 2/3 |
| Wide nasal bridge | 50% | 3/3 |
| Bulbous nose | 50% | 3/3 |
| Feeding difficulties | 50% | 3/3 |
| wide-spaced teeth | 25% | 3/3 |
| Large, fleshy hands | 50% | 3/3 |
| Hyperextensibility | 50% | 2/3 |
| Gastroesophageal reflux | 25% | 2/3 |
| Renal abnormalities | 38% | 1/3 |
| Cardiac defect | 3% to 25% | 0/3 |
| Seizures | 25% | 3/3 |
APhelan et al. [7] genetic counseling.
Germline mosaicism may be a significant mechanism for the generation of de novo pathogenic CNVs. If the 22q13.3 variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk in siblings is estimated to be 1% because of the theoretical possibility of parental germline mosaicism [1]. Indeed, prenatal testing and preimplantation genetic testing for PMS are possible for future pregnancies at increased risk [7].
Conclusion
In summary, the genotype-phenotype of PMS is still not clear. Moreover, the penetrance of this deletion seems to be incomplete for some genes, leading to variable phenotypes in patients with the same deletion. Sequencing of the genes localized in this region can identify variants in the remaining copy.