Two unrelated children with overlapping 6q25.3 deletions, motor speech disorders, and language delays

Abstract

Interstitial and terminal 6q25 deletions are associated with developmental delays, hypotonia, eye pathologies, craniofacial dysmorphologies, and structural brain anomalies. In most cases, speech and language deficits are not described in detail. We report on a case (Patient 1, age 7 years) with a de novo 6q25.3-qter deletion, 11.1 Mb long and encompassing 108 genes, and a case (Patient 2, age 5 years) with an inherited interstitial 6q25.3 deletion, located within Patient 1's deletion region and 403 kb long, the smallest 6q25 deletion reported to date. Both children have hypotonia, motor speech disorders, and expressive language delays. Patient 1's speech was characterized by childhood apraxia of speech (CAS) and dysarthria. Other findings include developmental delay, ataxic cerebral palsy, optic nerve dysplagia, and atypical brain morphologies regarding the corpus callosum and gyration patterns, a clinical profile that closely matches a previously reported case with a nearly identical deletion. Patient 2 had speech characterized by CAS and typical nonverbal processing abilities. His father, a carrier, had typical speech and language but showed difficulties with complex motor speech and hand motor tasks, similar to other adults with residual signs of CAS. The small deletion in this family contains the IGF2R-AIRN-SLC22A2-SLC22A3 gene cluster, which is associated with imprinting and maternal-specific expression of Igf2R, Slc22a2, and Slc22a3 in mice, whereas imprinting in humans is a polymorphic trait. The shared phenotypes in the two patients might be associated with the deletion of the gene cluster.

Sequential processing deficit as a shared persisting biomarker in dyslexia and childhood apraxia of speech

“…Further, all adults in the phCAS group had at least two biological relatives with a current CAS diagnosis and a family history of CAS. In two of these families, candidate genes have already been identified and the family members who participated in this study were carriers of the genetic variants, a CDH18 mutation on chromosome 5 in one family (Peter et al, 2016) and a heterozygously deleted IGF2R – AIRN - SLC22A2 – SLC22A3 gene cluster on chromosome 6 in another family (Peter et al, 2017). In an additional family, a different candidate region on chromosome 6 was identified (Peter et al, 2012).…”

Aetiology of childhood apraxia of speech: A clinical practice update for paediatricians

“…A clinical magnetic resonance imaging (MRI) to check for neurological lesions may also be indicated if dysarthria is suspected; children with isolated CAS do not show lesions on routine MRI. However, isolated CAS is rare, and in many cases, children demonstrate one or more of these other developmental speech disorders articulation, phonology dysarthria or even stuttering, alongside CAS …”

“…The discovery that variants of FOXP2 were associated with a rare and monogenic form of CAS catalysed the study of further genes for speech and language disorders. More than 15 years after the FOXP2 discovery, microarray and next‐generation technologies now enable rapid and relatively cost‐efficient genetic testing and have led to a proliferation of further discoveries of gene pathways associated with CAS …”

“…To highlight the rapidly growing aetiological knowledge in this field, and the presence of significant neurodevelopmental comorbidity for many cases with CAS, we will illustrate genotype–phenotype associations for a handful of single‐gene variant and copy number‐variant conditions associated with CAS (Table ). It was beyond the scope of this article to provide an exhaustive summary of all neurogenetic syndromes, copy number‐variant conditions or even chromosomal rearrangements associated with CAS; however, CAS has been associated with conditions such as Floating‐Harbor syndrome, Cri du chat syndrome, galactosaemia, 6q25.3 deletion, 7q11.23 duplication and chromosomal translocations . Moreover, we have not covered recently identified genes for CAS, where replication or further evidence of the relevance of these candidates to the broader population of CAS is not yet clear …”

“…However, isolated CAS is rare, and in many cases, children demonstrate one or more of these other developmental speech disorders articulation, phonology dysarthria or even stuttering, alongside CAS. [13][14][15][16] Final important considerations of a CAS diagnosis include that: (i) features of CAS tend to be less severe with age, with sounds and syllables being co-articulated more clearly and efficiently (although altered prosody remains a hallmark); (ii) there is heterogeneity in the severity and specific type of symptomatology across the population; and (iii) it is more challenging to provide a reliable CAS diagnosis when it co-occurs with other neurodevelopmental disorders, particularly in children who are largely non-verbal at older age ranges, such as often occurs in autism or global developmental delay.…”