Skip to main content

Conference Program

Subpage Hero

Loading

Partial de novo SOX6 duplication in a patient with macrocephaly, overgrowth and developmental regression

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
We report a patient with autism and a partial duplication of SOX6 (de novo) that has not been associated with a clinical phenotype.

 

Humans have nineteen SOX or SRY-related HMG box (SOX)- containing genes which play an important role in determining cell-fate and identity in many lineages during embryonic development. Mutations in several SOX genes have been reported to be associated with congenital anomalies and/or neurodevelopmental disorders (SOX2, 3, 4, 5, 6, 9, 10, 11, 17, 18.). The mutations are typically de novo and include those causing haploinsufficiency, but other mutation types, including duplications have been reported in SOX 3, 8 and 9 (Angelozzi M, Lefebvre V, 2019). The most frequent are missense variants in the HMG domain which mediates DNA-binding, nuclear trafficking and protein-protein interaction. The SOX6 HMG domain (exons 14-15) are duplicated in our patient.

 

Case Presentation
The proband is a 2-year-old boy with macrocephaly, global developmental delays, autism and developmental regression. He had bilateral inguinal hernia. Macrocephaly was recognized at 9 months of age (Z score= 3.2). He was on target for early developmental milestones: walked and said his first words at 11 months and had a vocabulary of 20 words at 15 months of age. An evaluation for staring spells at 20 months included a video EEG that showed no association with epileptic changes.

 

He had regression of language skills at 23 months and was diagnosed with autism spectrum disorder. He is treated with multiple medications for insomnia.  

 

He was delivered at term by C-section for failure to progress after a pregnancy complicated by maternal pregnancy-induced hypertension and preeclampsia. BW was 7lb 1 oz. There were no postnatal complications. Family history was pertinent for ADHD in mother and for father being overweight. Neither had macrocephaly.

 

Macrosomia was noted in patient at age 27 mos (Z score weight= 3.13; for height= 1.51, Z score for HC= 4). At age 4, he continues to have macrocephaly and macrosomia (Z score HC= 5.6, weight= 5.19, height= 2.17).

 

Diagnostic Workup
A head ultrasound (9 mos) was reported to be normal. Brain MRI (age 20 mos) showed nonspecific scattered periventricular and subcortical white matter T2 hyperintensities, but was otherwise normal.

Chromosome microarray analysis detected a 5.42 Mb interstitial duplication at 11p15.3p15.1: arr[hg19] 11p15.3p15.1(10,887,467-16,306,448)x3 dn

The duplicated interval of uncertain significance does not include the 11p15 imprinted region associated with BWS and disrupts the SOX 6 gene.

Gene-targeted testing showed two intragenic duplications of exons 4-9 and 13-16.

SOX6 NM_033326.3: Duplication of Exons 4-9; Unknown Significance

SOX6 NM_033326.3: Duplication of Exons 13-16; Unknown Significance

Trio Exome Sequencing: No causative variants identified related to patient’s clinical features.

 

Outcome and Follow-Up


 

Discussion
Heterozygous loss of function variants in SOX6 are associated with SOX6-related neurodevelopmental disorders characterized by intellectual disability, most often mild-moderate, autism, ADHD and skeletal abnormalities including craniosynostosis and osteochondromas. Other birth defects were rare and the growth parameters were average in the majority of reported patients (Tolchin D et al., 2020).

 

 

Conclusion
Our patient with partial duplication of SOX6 has overlapping clinical features of autism and intellectual disability. He also has significant macrocephaly. We propose that this variant causes or contributes to our patient’s clinical features.

 

References: Tolchin D, et al, 2020 De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas. Am J Hum Genet. 2020 Jun 4;106(6):830-845.

SOXopathies: Growing Family of Developmental Disorders Due to SOX Mutations. Trends Genet. 2019 Sep;35(9):658-671.

Agenda

Sponsors