Case Report: Expressive Speech Disorder in a Family as a Hallmark of 7q31 Deletion Involving the FOXP2 Gene

Abstract

Pathogenic variants of FOXP2 gene were identified first as a monogenic cause of childhood apraxia of speech (CAS), a complex disease that is associated with an impairment of the precision and consistency of movements underlying speech, due to deficits in speech motor planning and programming. FOXP2 variants are heterogenous; single nucleotide variants and small insertions/deletions, intragenic and large-scale deletions, as well as disruptions by structural chromosomal aberrations and uniparental disomy of chromosome 7 are the most common types of mutations. FOXP2-related speech and language disorders can be classified as “FOXP2-only,” wherein intragenic mutations result in haploinsufficiency of the FOXP2 gene, or “FOXP2-plus” generated by structural genomic variants (i.e., translocation, microdeletion, etc.) and having more likely developmental and behavioral disturbances adjacent to speech and language impairment. The additional phenotypes are usually related to the disruption/deletion of multiple genes neighboring FOXP2 in the affected chromosomal region. We report the clinical and genetic findings in a family with four affected individuals having expressive speech impairment as the dominant symptom and additional mild dysmorphic features in three. A 7.87 Mb interstitial deletion of the 7q31.1q31.31 region was revealed by whole genome diagnostic microarray analysis in the proband. The FOXP2 gene deletion was confirmed by multiplex ligation-dependent probe amplification (MLPA), and all family members were screened by this targeted method. The FOXP2 deletion was detected in the mother and two siblings of the proband using MLPA. Higher resolution microarray was performed in all the affected individuals to refine the extent and breakpoints of the 7q31 deletion and to exclude other pathogenic copy number variants. To the best of our knowledge, there are only two family-studies reported to date with interstitial 7q31 deletion and showing the core phenotype of FOXP2 haploinsufficiency. Our study may contribute to a better understanding of the behavioral phenotype of FOXP2 disruptions and aid in the identification of such patients. We illustrate the importance of a targeted MLPA analysis suitable for the detection of FOXP2 deletion in selected cases with a specific phenotype of expressive speech disorder. The “phenotype first” and targeted diagnostic strategy can improve the diagnostic yield of speech disorders in the routine clinical practice.

Keeping the balance: Trade-offs between human brain evolution, autism, and schizophrenia

“…There are several protein-coding loci within the 7q31–q33 region including RNF148 , RNF133 , and CADPS 2 ; the latter being particularly interesting from the clinical and evolutionary standpoints. In human, deletions as well as amplifications of the genetic interval containing CADPS2 (Ca 2+ -dependent activator protein for secretion 2) have been associated to ASD ( Bonora et al, 2014 ; Grabowski et al, 2017 ; Nagy et al, 2021 ). Interestingly, CADPS2 can be aberrantly spliced in ASD in autistic patients ( Sadakata et al, 2007 ).…”

Differences and Commonalities in Children with Childhood Apraxia of Speech and Comorbid Neurodevelopmental Disorders: A Multidimensional Perspective

“…Regarding etiology, increasing evidence suggests that CAS has a genetic basis. Mutations in FOXP2, originally described in the multigenerational KE family [7], account for a small proportion of cases [8,9]. The use of chromosome microarray analysis (CMA) and the application of next generation sequencing techniques have denoted a large genetic heterogeneity in the past few years [10][11][12][13][14][15][16] with the identification of gene variants that may implicate shared pathways in broad transcriptional regulation during normal speech development [16][17][18][19][20].…”