SOX5: Lamb–Shaffer syndrome—A case series further expanding the phenotypic spectrum

Abstract

Objective: To delineate further the clinical phenotype of Lamb-Shaffer Syndrome (LSS) Methods: 16 unpublished patients with heterozygous variation in SOX5 were identified either through the UK Decipher database or the study team was contacted by clinicians directly. Clinical phenotyping tables were completed for each patient by their responsible clinical geneticist. Photos and clinical features were compared to assess key phenotypes and genotype-phenotype correlation. Results: We report 16 SOX5 variants all of which meet American College of Medical Genetics/Association for Clinical Genomic Science ACMG/ACGS criteria class IV or V. 7/16 have intragenic deletions of SOX5 and 9/16 have single nucleotide variants (including both truncating and missense variants). The cohort includes two sets of monozygotic twins and parental gonadal mosaicism is noted in one family. Conclusions: This cohort of 16 patients is compared with the 7160 previously reported cases and corroborates previous phenotypic findings. As expected, the most common findings include global developmental delay with prominent speech delay, mild to moderate intellectual disability, behavioural abnormalities and sometimes subtle characteristic facial features. We expand in more detail on the behavioural phenotype and observe that there is a greater tendency towards lower growth parameters and microcephaly in patients with single nucleotide variants. This cohort provides further evidence of gonadal mosaicism in SOX5 variants; this should be considered when providing genetic counselling for couples with one affected child and an apparently de novo variant.

Lamb–Shaffer syndrome: 20 Spanish patients and literature review expands the view of neurodevelopmental disorders caused by SOX5 haploinsufficiency

“…After literature mining, a total of 111 patients were reviewed including the new cohort of 20 reported here 1,12,[17][18][19][20][21][22][23][24][25][26][27] (Table 1, Supplementary Table 2). Gender distribution was similar between groups (59 males and 52 females) and the mean age at diagnosis (calculated in available cases) was 6.9 ± 3 years (Figure 3.…”

“…Although a clear genotype-phenotype correlation has not been seen, it seems that large copy number variations (CNVs) can cause a more severe phenotype, probably due to the affection of more than one gene, than intragenic variants, and truncating variants seem to be more frequently associated with both smaller growth parameters and head circumferences than 12p microdeletions CNVs. 12 The diagnosis of LSS is usually made based on clinical features, such as the presence of DD, ID, visual problems, dysmorphic features, autistic features and the genetic testing to confirm the presence of pathogenic or likely pathogenic variants in SOX5. However, because this syndrome is very infrequent and many of the features can be subtle or overlap with other disorders, it is frequently undiagnosed or misdiagnosed for years.…”

“…Although a clear genotype–phenotype correlation has not been seen, it seems that large copy number variations (CNVs) can cause a more severe phenotype, probably due to the affection of more than one gene, than intragenic variants, and truncating variants seem to be more frequently associated with both smaller growth parameters and head circumferences than 12p microdeletions CNVs 12 …”