7q31.2q31.31 deletion downstream of FOXP2 segregating in a family with speech and language disorder

Abstract

Chromosomal 7q31 deletions have been described in individuals with variable neurodevelopmental phenotypes including speech and language impairment. These copy number variants usually encompass FOXP2, haploinsufficiency of which represents a widely acknowledged cause for specific speech and language disorders. By chromosomal microarray analysis we identified a 4.7 Mb microdeletion at 7q31.2q31.31 downstream of FOXP2 in three family members presenting with variable speech, language and neurodevelopmental phenotypes. The index individual showed delayed speech development with impaired speech production, reduced language comprehension, and additionally learning difficulties, microcephaly, and attention deficit. His younger sister had delayed speech development with impaired speech production and partially reduced language comprehension. Their mother had attended a school for children with speech and language deficiencies and presented with impaired articulation. The deletion had occurred de novo in the mother, includes 15 protein-coding genes and is located in close proximity to the 3 0 end of FOXP2. Though a novel locus at 7q31.2q31.31 associated with mild neurodevelopmental and more prominent speech and language impairment is possible, the close phenotypic overlap with FOXP2-associated speech and language disorder rather suggests a positional effect on FOXP2 expression and function.

A 9.8 Mb deletion at 7q31.2q31.31 downstream of FOXP2 in an individual with speech and language impairment suggests a possible positional effect

“…A 4.7 Mb deletion at 7q31.2q31.31, overlapping our proband's deletion, has been reported in three members of a family with speech and language issues, learning difficulties, microcephaly, and ADHD. 19 The shared deleted region contains 13 OMIM genes, and both deletions are located 550 ~ 600 kb downstream of the FOXP2 gene. In addition, a 3.2 Mb deletion overlapping our proband's deletion has been identified in a girl with developmental delay and hearing loss.…”

“…The 13 OMIM genes in the deleted region shared among these previously reported patients and the current patient were reviewed in previous studies and in our study. 1 , 19 Among them are three disease‐causing genes, CFTR , MET , and CAV1 . None of these genes have been implicated yet in language development.…”

“…Given the absence of definitive candidate genes within the deletion for the proband's phenotypes, we propose the FOXP2 gene is involved in our proband's language‐related phenotypes via a positional effect, in agreement with the previously reported case. 19 FOXP2 may be also responsible for proband's other features such as developmental delay and cognitive impairment that falls within a broad spectrum of FOXP2 ‐related disorders. 3 The proband's father has a history of learning issues, seizures, abnormal speech, and Tourette syndrome, which suggests variable expressivity.…”

“…The 15 protein‐coding genes included in the deletion have no known implications in language disorder, and phenotypes of the affected individuals overlapped highly with those in FOXP2 ‐related language and speech disorder, suggesting the involvement of FOXP2 in pathogenesis, likely due to positional effects on the gene. 19 Here, we report a 6‐year‐old girl with language impairment, global developmental delay, relative microcephaly, attention deficit/hyperactivity disorder (ADHD), and learning difficulties with a heterozygous 9.8 Mb deletion at 7q31.2‐q31.33 that is located 550 kb downstream of the FOXP2 gene. The deletion was inherited from her father, who also has a history of abnormal speech and learning disabilities.…”

Indepth characterization of a cohort of individuals with missense and loss-of-function variants disruptingFOXP2

“…There are other variants that affect FOXP2 that are not SNVs or indels. A large deletion downstream of FOXP2 was hypothesised to have a position effect on expression (6). There have also been case series of large heterozygous 7q31 deletions or reciprocal balanced translocations associated with more complex phenotypes involving disruptions of FOXP2 in addition to neighbouring genes (7)(8)(9)(10)(11)(12)(13)(14)(15).…”