Childhood apraxia of speech, oral motor apraxia, and velopharyngeal insufficiency in a young woman with a de novo pathogenic variant in the ZNF292 gene

The ZNF292 gene encodes a zinc-finger protein that is strongly expressed in the brain during prenatal development.^{1, 2} ZNF292-related neurodevelopmental disorder (NDD) was delineated in a cohort of 28 individuals with 24 different variants in ZNF292.² Our patient displays several prominent features of NDD including intellectual disability (ID), speech/language delays, and autism spectrum disorder (ASD). She also has more significant motor delay and difficulties with coordination associated with hypotonia and chewing/swallowing difficulties from an early age associated with velopharyngeal insufficiency (VPI), oral motor apraxia (OMA), and childhood apraxia of speech (CAS).

This 16-year-old Caucasian female was evaluated for a long-standing history of speech delay with gross and fine motor delay and dyscoordination and hypotonia. She had a history of dysphagia and nasal regurgitation of liquids, characterized as OMA and VPI by otolaryngology and speech pathology. Multiple speech pathology assessments were performed from early childhood until the time of her evaluation due to expressive language delay with poor intelligibility associated with motor planning difficulties, consistent with childhood apraxia of speech. Her math and reading skills were at a grade 7 level. There was no history of seizures or cardiac conditions.

In her late teens, she was formally diagnosed with ASD. Neuropsychological testing showed overall ID from borderline to average ranges with a full-scale IQ of 86. Attention/executive function testing was average.

She was a slender young lady with minor dysmorphic features including relatively small ears, a bulbous nasal tip, relatively large lips and mouth with thin upper lip, and long slender fingers. She was able to respond to questions although her speech was hypernasal and difficult to understand. She had difficulties with tongue protrusion and imitating tongue movements, and she was not able to puff her cheeks, consistent with her history of oromotor apraxia. Her neurological examination was significant for hypotonia with normal resistive strength and normal deep tendon reflexes.

Magnetic resonance imaging of the brain showed a normal myelination pattern without cortical malformation. A GeneDx ID/ASD expanded panel at age 16 years was negative. Reanalysis of the GeneDx panel, at age 22, revealed a de novo pathogenic variant in the ZNF292 gene [c.3432_3436del; p.(N1114Kfs*5)]. Both parents did not carry the variant. This specific variant has not been reported in the literature.

This patient expands upon the previously described phenotypes associated with ZNF292-related NDD (Table 1).² The phenotypic expression is variable except for almost universal presentations of ID (96%) and speech delays (93%) as well as autistic features (61%). Our patient had speech delays and autistic features with relatively spared ID. ID and ASD are common presentations in neurology clinics. Therefore, it is imperative to identify genes associated with ID and ASD and to report novel genetic findings since determining underlying genetic causes can improve patients' quality of life by better managing comorbid medical conditions,³ such as those summarized in Table 1.

Feeding difficulties, although not elaborated on by Mirzaa et al., were present in one-third of patients. Our patient had early feeding difficulties associated with VPI and OMA as well as speech delay characterized by CAS.

Mirzaa's publication does not discuss the incidence of OMA, CAS, and VPI in patients with ZNF292. Ours is the first report of these specific conditions associated with a ZNF292 gene variant. It is likely that undiagnosed OMA, CAS, and VPI may be present in other patients described with this condition as a cause of feeding difficulties and expressive language delay. A recent review of genetic causes of CAS did not identify any children with ZNF292 in their cohort. A novel de novo pathogenic variant [c.3432_3436del; p.(N1114Kfs*5)] was discovered in our patient, which has not been previously described. The expanding list of genes associated with CAS highlights the importance of performing genetic testing for monogenic disorders.⁴

Our report expands the documented phenotypes associated with ZNF292-related NDD by characterizing more fully the feeding and speech difficulties as OMA, VPI, and CAS. This report also expands the list of genes to consider in the differential diagnosis of ID, ASD, and CAS.

Jessica M. Davis: Writing—original draft. Deborah L. Renaud: Supervision; writing—review and editing.