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Review
. 2023 Feb 21;14(3):540.
doi: 10.3390/genes14030540.

Head Size in Phelan-McDermid Syndrome: A Literature Review and Pooled Analysis of 198 Patients Identifies Candidate Genes on 22q13

Sara M Sarasua  1 , Jane M DeLuca  1 , Curtis Rogers  2 , Katy Phelan  3 , Lior Rennert  4 , Kara E Powder  5 , Katherine Weisensee  6 , Luigi Boccuto  1
Affiliations
Review

Head Size in Phelan-McDermid Syndrome: A Literature Review and Pooled Analysis of 198 Patients Identifies Candidate Genes on 22q13

Sara M Sarasua et al. Genes (Basel). .

Abstract

Phelan-McDermid syndrome (PMS) is a multisystem disorder that is associated with deletions of the 22q13 genomic region or pathogenic variants in the SHANK3 gene. Notable features include developmental issues, absent or delayed speech, neonatal hypotonia, seizures, autism or autistic traits, gastrointestinal problems, renal abnormalities, dolichocephaly, and both macro- and microcephaly. Assessment of the genetic factors that are responsible for abnormal head size in PMS has been hampered by small sample sizes as well as a lack of attention to these features. Therefore, this study was conducted to investigate the relationship between head size and genes on chromosome 22q13. A review of the literature was conducted to identify published cases of 22q13 deletions with information on head size to conduct a pooled association analysis. Across 56 studies, we identified 198 cases of PMS with defined deletion sizes and head size information. A total of 33 subjects (17%) had macrocephaly, 26 (13%) had microcephaly, and 139 (70%) were normocephalic. Individuals with macrocephaly had significantly larger genomic deletions than those with microcephaly or normocephaly (p < 0.0001). A genomic region on 22q13.31 was found to be significantly associated with macrocephaly with CELSR1, GRAMD4, and TBCD122 suggested as candidate genes. Investigation of these genes will aid the understanding of head and brain development.

Keywords: 22q13 deletion; Phelan–McDermid syndrome; genotype-phenotype correlation; head circumference; macrocephaly; microcephaly.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Distribution of deletions for individuals with macrocephaly (top), microcephaly (middle), and normocephaly (lower) with SHANK3 preserved. The graphic demonstrates the preponderance of deletions in the 22q13.2 and 22q13.31 bands for those with macrocephaly whereas individuals with normocephaly have deletions across all of 22q13. No pattern of deletions is apparent for microcephaly among those with SHANK3 preserved.
Figure 2
Figure 2
Distribution of deletions for individuals with macrocephaly (top), microcephaly (middle), and normocephaly (bottom panel) with SHANK3 partially or completely deleted. Note the preponderance of deletions > 1 Mb among individuals with microcephaly compared to those with normocephaly. Note the preponderance of deletions > 4 Mb among those with macrocephaly.
Figure 3
Figure 3
Distribution of OFC percentile by chromosome 22q13 deletion size for 87 individuals with partially or fully deleted SHANK3.
See this image and copyright information in PMC

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