Exome sequencing expands the mechanism of SOX5‐associated intellectual disability: A case presentation with review of sox‐related disorders

Abstract

The SOX5 haploinsufficiency syndrome is characterized by global developmental delay, intellectual disability, language and motor impairment, and distinct facial features. The smallest deletion encompassed only one gene, SOX5 (OMIM 604975), indicating that haploinsufficiency of SOX5 contributes to neuro developmental delay. Although multiple deletions of the SOX5 gene have been reported in patients, none are strictly intragenic point mutations. Here, we report the identification of a de novo loss of function variant in SOX5 identified through whole exome sequencing. The proband presented with moderate developmental delay, bilateral optic atrophy, mildly dysmorphic features, and scoliosis, which correlates with the previously-described SOX5-associated phenotype. These results broaden the diagnostic spectrum of SOX5-related intellectual disability. Furthermore it highlights the utility of exome sequencing in establishing an etiological basis in clinically and genetically heterogeneous conditions such as intellectual disability.

Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice

“…Besides, hypoplasia of n.opticus was suspected based on ophtalmological evaluation. Based on characteristic features (developmental delay, microcephaly, mild dysmorphic features including strabismus, and n.opticus hypoplasia), Lamb‐Shaffer syndrome was diagnosed . Although most of the described patients had whole‐gene or intragenic deletions of SOX5 gene, recently a patient with a de novo missense variant SOX5:c.1831C > G; p.(Arg611Gly) was identified in a patient with intellectual disability, slightly pale optic discs and mild dysmorphic features …”

Tcf4 encodescortical differentiation during development

“…Confirming the data previously shown and described above, GO-term analysis (PANTHER Over-representation Test, Figure 8A) shows that Tcf4 is involved in the regulation of (neuronal) differentiation, cell signaling, synaptic plasticity, and development of the telencephalon and hippocampus. Further analysis of the genes regulated by Tcf4 shows that 26 of the 137 genes regulated by Tcf4 (19%) have previously been shown to be mutated in cases of ID (Figure 8B) (Alders et al, 2014;Backx et al, 2010;Brockschmidt et al, 2007;Cocchella et al, 2010;Ehmke et al, 2017;Gerber et al, 2016;Gillentine et al, 2017;Guo et al, 2016;Labonne et al, 2016;Magoulas and El-Hattab, 2012;Merla et al, 2002;Metsu et al, 2014;Mikhail et al, 2011;Montesinos, 2014;Moore et al, 2016;Mulatinho et al, 2012;Myers et al, 2012;Nesbitt et al, 2015;Poot et al, 2010;Schoonjans et al, 2016;Schuurs-Hoeijmakers et al, 2013;Srivatsa et al, 2014;Tassano et al, 2015;Thevenon et al, 2014;Ţuţulan-Cunită et al, 2012). Characteristics of these cases range from moderate to severe ID, autistic phenotypes, brain malformations, speech impairments, and epilepsy.…”

Genome‐wide association study and heritability estimate for ectopic ureters in Entlebucher mountain dogs

“…Coding variants may lead to Lamb‐Shaffer syndrome in humans, a neurodevelopmental disorder, sometimes seen in combination with variable skeletal abnormalities (Nesbitt et al . ) but extremely rarely with urogenital malformations (Lee et al . ).…”