A number sign (#) is used with this entry because of evidence that hypotonia, ataxia, and delayed development syndrome (HADDS) is caused by heterozygous mutation in the EBF3 gene (607407) on chromosome 10q26.

Hypotonia, ataxia, and delayed development syndrome (HADDS) is a neurodevelopmental syndrome characterized by congenital hypotonia, delayed psychomotor development, variable intellectual disability with speech delay, variable dysmorphic facial features, and ataxia, often associated with cerebellar hypoplasia. Some patients may have urogenital abnormalities (summary by Sleven et al., 2017).

Harms et al. (2017) reported 10 patients from 9 unrelated families with global developmental delay, intellectual disability, and speech delay apparent from infancy. The patients ranged in age from 2 to 25 years. Most patients had early truncal hypotonia and later developed ataxia. Brain imaging in most patients was normal, but 2 had cerebellar hypoplasia. There were common, but variable, mild dysmorphic features, including tall forehead, long face, deep philtrum, high nasal bridge, straight eyebrows, strabismus, low-set and posteriorly rotated ears, and short or broad chin. Two sibs had seizures.

Chao et al. (2017) reported 3 unrelated children, a boy and 2 girls, with global developmental delay, intellectual disability, expressive speech disorder with dysarthria, dysphagia, congenital hypotonia with poor head control, delayed walking, and ataxia. One child was a Pacific Islander of Chinese and Japanese descent, another was of African American descent, and the third was of European descent. Two of the mothers reported reduced fetal movements. The patients also had variable mild dysmorphic features including oval or triangular myopathic facies, overfolding of the superior helices of the ears, low-set ears, anteverted nostrils, epicanthal folds, downturned corners of the mouth, and strabismus. In addition, the boy had micropenis, cryptorchidism, and testicular failure, and one of the girls had a mild reduction in the volume of the labia majora. Brain imaging in 2 patients showed cerebellar hypoplasia, but imaging was normal in the third patient. Two patients had pain insensitivity, and all showed some type of stereotypic behavior. More variable features included astigmatism, gastroesophageal reflux, inverted nipples, mild vesicoureteral reflux, dysmetria, and apraxia.

Sleven et al. (2017) reported 8 children from 7 unrelated families with global developmental delay, hypotonia, delayed walking, and ataxia. The patients had mild intellectual disability with variably delayed speech, but 4 attended mainstream schools and 4 attended special schools. Dysmorphic facial features were variable, but included prominent forehead, straight eyebrows, synophrys, deep-set eyes, strabismus, tubular-shaped nose, broad nasal tip, thin upper lip, downturned mouth, and low-set ears. Four patients had short stature and 2 had microcephaly. Three patients had vesicoureteral reflux, 1 had left cryptorchidism, and 1 had a high pain threshold. Four patients had normal brain imaging, 1 had cerebellar hypoplasia, 1 had delayed myelination, and 1 had subtle dysplasia of the cerebellar cortex.

Deisseroth et al. (2022) reported a phenotypic assessment of 41 patients with HADDS and mutations in the EBF3 gene. Delayed language and motor developmental findings were often seen. Over 97% of patients had speech delay with over 85% of individuals having delays in expressive language. Motor features included hypotonia (100%), delayed motor development (98%), ataxia (78%), incoordination (63%), and hypertonia (39%). EEG abnormalities were seen in 34% of patients; 20% had febrile seizures and 15% had unprovoked seizures. A chronic decreased pain response was seen in 95% of patients, with other sensory features (e.g., repetitive itching behaviors in 54%). Neuropsychiatric findings included autistic features in 68%, with formally diagnosed autism in 27%. The most frequently affected brain structure was the cerebellum, which was seen in 29% of patients. Craniofacial features were seen in 83%, constipation in 88%, gastroesophageal reflux in 59%, and strabismus in 88%. Urinary tract infections were common (seen in 46%), with recurrent urinary tract infections in 44% of patients.

The heterozygous mutations in the EBF3 gene that were identified in 8 unrelated patients with HADDS by Harms et al. (2017) occurred de novo.

Two sibs with HADDS reported by Harms et al. (2017) inherited a heterozygous mutation in the EBF3 gene from their unaffected mother who was mosaic for the mutation.

In 2 sibs with hypotonia, ataxia, and delayed development syndrome, Harms et al. (2017) identified a heterozygous mutation in the EBF3 gene (607407.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from an unaffected mother who was mosaic for the mutation. The authors reported 8 additional patients with HADDS; the variants in these patients, all of which occurred de novo (see, e.g., 607407.0002-607407.0004), were said to have been identified through whole-exome sequencing by groups that independently submitted to GeneMatcher. There were 5 missense mutations, all of which occurred at highly conserved residues in the DNA-binding domain, and 4 frameshift, splice site, or nonsense mutations. In vitro functional expression studies showed that the mutations resulted in significantly reduced ability to activate transcription of a reporter gene. Some mutations demonstrated a dominant-negative effect, whereas others appeared to result in a loss of function. The findings showed that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay.

In 3 unrelated children with HADDS, Chao et al. (2017) identified de novo heterozygous missense mutations affecting the same residue in the EBF3 gene (R163Q, 607407.0005 and R163L, 607407.0006). The mutations were found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the R163Q variant resulted in complete loss of function, whereas R163L was a hypomorphic allele. Neither variant was able to rescue the embryonic lethality and defects in development of the nervous system in Drosophila with homozygous loss of the Ebf3 homolog ('knot' or 'collier'), indicating that the mutations resulted in a loss of function. Chao et al. (2017) noted that EBF3 is transcriptionally repressed by ARX (300382), and that gain-of-function mutations in ARX, which would suppress EBF3, cause overlapping neurodevelopmental disorders, suggesting a common transcriptional cascade pathway.

In 8 patients from 7 unrelated families with HADDS, Sleven et al. (2017) identified heterozygous mutations in the EBF3 gene (see, e.g., 607407.0003; 607407.0007-607407.0010). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Mutations in 6 patients occurred de novo; 2 affected sibs inherited a mutation from a mosaic parent. The variants included 3 missense and 2 splice site mutations, a frameshift mutation, and a nonsense mutation. In vitro functional studies of the missense mutations showed that they resulted in impaired EBF3 transcription function compared to wildtype. The mutant missense proteins were able to form a heterodimer with wildtype EBF3, suggesting that they may have a dominant-negative effect. However, Sleven et al. (2017) concluded that the mechanism of action is most likely related to loss of function, leading to a reduction in transcriptional activation of EBF3 early in development.

Deisseroth et al. (2022) performed a genotypic assessment of 41 patients with variation affecting the EBF3 gene. Twenty-seven patients (66%) had a de novo mutation, 5 patients had an affected parent (4 mothers and 1 father), and 2 patients had affected parents with mosaicism (1 mother and 1 father). In 7 patients, inheritance was either unknown or the family opted out of testing. Among their cohort of 41 patients, 7 had noncoding EBF3 variants, 2 had 10q26 deletions (609625) disrupting the EBF3 locus, and 32 had coding EBF3 variants. The authors also reviewed 47 previously reported patients with an EBF3 mutation and identified 5 with noncoding variants, 5 with 10q26 deletions disrupting the EBF3 gene, and 37 with coding EBF3 variants. Overall, the majority of the EBF3 variants clustered within the N-terminal DNA-binding domain, many of which were within 5 amino acids of the zinc finger domain, which is required for stabilizing the interaction between EBF3 and the DNA target. Nine unrelated individuals (10% of those with pathogenic EBF3 variants) affected the arginine residue at position 163 (R163Q, 607407.0005 in 4; R163P, 607407.0007 in 2; R163W in 2, and R163L, 607407.0006 in 1). Other recurrent variants included ones that affected the arginine residue at position 209 in 9 individuals, including R209W (607407.0001) in 5 patients. Deisseroth et al. (2022) postulated that these de novo variants may be recurrent due to their position in CpG-dinucleotide islands, which are mutation hotspots. The authors performed in vivo studies in fruit flies and in vitro studies of transcriptional activation. Variants affecting the zinc finger domain were unable to restore viability in the fruit fly and impaired transcriptional activation, whereas the recurrent R209W variant, which affects the DNA-binding domain, was able to partially rescue fruit fly viability and preserved transcriptional activation.

In a review of 41 patients with HADDS, Deisseroth et al. (2022) identified a correlation between symptom severity risk and missense variants primarily disrupting the EBF3 zinc finger domain.