Rare LAMA5 variant is the likely cause of a severe speech and reading disorder in a de novo case

Childhood apraxia of speech (CAS) is a rare and severe form of speech sound disorder that is frequently comorbid with dyslexia. There is evidence that CAS has a genetic etiology, but causal DNA variations have only been... [ view full abstract ]

Childhood apraxia of speech (CAS) is a rare and severe form of speech sound disorder that is frequently comorbid with dyslexia. There is evidence that CAS has a genetic etiology, but causal DNA variations have only been identified in a few cases. Here, we describe a child age 9 years with CAS and extremely poor reading and spelling abilities; there was no family history of speech or language disorder. The phenotype was further characterized by poor fine and gross motor coordination and poor motor speech control, especially regarding integrating complex motor commands. Together, these traits are consistent with cerebellar dysfunction. Exome sequences were obtained for the child and both biological parents. Exomes were annotated with VEP and filtered with Gemini. De novo variant analysis yielded three validated variants. Of these, most likely to be pathogenic is an extremely rare missense variant in the LAMA5 gene at bp position 60,921,247. This variant is not reported in dbSNP and is predicted to be deleterious (scaled CADD = 22.7). LAMA5 is associated with encoding of the vertebrate laminin alpha chains. A homozygous sequence variant in LAMA5 has been associated with a failure of neuromuscular transmission and central nervous system (CNS) manifestations. LAMA5 is highly expressed in the cerebellum (median RPKM = 41.2). In addition, 19 validated X-linked recessive variants were found. Of these, one is rare, predicted to be deleterious (CADD = 22.7), and situated in a gene involved in neurogenesis, which is NLGN4X.  Of 85 validated autosomal recessive variants, one is a splice variant in VWA3B, which has been associated with cerebellar ataxia and intellectual disability. Together, these results are consistent with a monogenic or possibly polygenic etiology of CAS that is expressed in the cerebellum and has downstream effects on abilities under cerebellar control, including conversational speech, motor speech control, reading, and fine and gross motor control. Future studies should extend these findings by evaluating cerebellar structures and functions using MRI technology.