A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH) is caused by homozygous or compound heterozygous mutation in the MADD gene (603584) on chromosome 11p11.

Biallelic mutation in the MADD gene can also cause a more severe neurodevelopmental disorder with some overlapping and additional systemic features (DEEAH; 619004).

Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH) is an autosomal recessive disorder characterized by global developmental delay and mildly to severely impaired intellectual development with poor speech and language acquisition. Some patients may have early normal development with onset of the disorder in the first years of life. More variable neurologic abnormalities include hypotonia, seizures, apnea, mild signs of autonomic or peripheral neuropathy, and autism. Aside from dysmorphic facial features and occasional findings such as scoliosis or undescended testes, other organ systems are not involved (summary by Schneeberger et al., 2020).

Anazi et al. (2017) reported a 6-year-old girl (17DG0770), conceived via IVF, with NEDDISH. She had normal early development until about 15 months of age when she showed speech delay, poor eye contact, and impaired social interaction compared to her unaffected dizygotic twin brother. She was diagnosed with autism spectrum disorder and continued to show speech delay, sleep disturbances, and behavioral abnormalities. Her twin brother was also mildly delayed, but not studied further.

Hu et al. (2019) reported 2 adult sisters, born of unrelated Iranian parents (family M135) with NEDDISH. Early development was normal, and both learned to walk and talk at 12 months of age. At 22 and 30 years of age, they showed impaired intellectual development (IQs of 50 and 60) and could build 2-word phrases, count money, and follow simple commands. Neither had seizures, spasticity, or behavioral abnormalities. Both had macrocephaly (+4 SD) and a long face or square mandible.

Schneeberger et al. (2020) reported 9 patients (patients 15-23) from 6 families (families 12-17) with NEDDISH. The patients, who ranged from 1 month to 19 years of age, all had global developmental delay, although the severity was highly variable. Two sibs (family 14) had mild intellectual disability at 13 and 19 years of age, whereas the rest of the patients had moderate to severe impairment. A few had behavioral abnormalities, such as ADHD or autistic features. Most had mildly delayed walking, sometimes with a dystonic gait, and all except 1 had impaired speech, including 2 patients who were nonverbal. Five patients had seizures, including 2 with absence and 2 with generalized; the fifth patient had only 1 episode of seizures. Other common features included hypotonia and nonspecific dysmorphic features, such as dolichocephaly, plagiocephaly, high or broad forehead, broad nasal bridge, full cheeks, low-set ears, small mouth, high palate, and dental crowding. Brain imaging was essentially normal, although 2 patients showed delayed myelination. Affected males had small penis and undescended testes. Less common features included kyphosis/scoliosis, apneic episodes in the neonatal period, and reduced pain sensation, suggesting neuropathy. None had endocrine abnormalities.

The transmission pattern of NEDDISH in the families reported by Schneeberger et al. (2020) was consistent with autosomal recessive inheritance.

In a 6-year-old girl (17DG0770) with NEDDISH, Anazi et al. (2017) identified compound heterozygous mutations in the MADD gene (R198H, 603584.0001 and R327X, 603584.0002). The mutations, which were found by exome sequencing of 68 families with intellectual disability, were confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed, but the nonsense mutation was predicted to disrupt the DENN domain including the GTPase binding site.

In 2 adult sisters, born of unrelated Iranian parents (family M135), with NEDDISH, Hu et al. (2019) identified compound heterozygous mutations in the MADD gene (603584.0003 and 603584.0004). The mutations were found by exome sequencing and confirmed by Sanger sequencing. The family was part of a large cohort of 404 consanguineous families, mostly Iranian, in which 2 or more offspring had impaired intellectual development. Functional studies of the variants and studies of patient cells were not performed.

In 9 patients (patients 15-23) from 6 families (families 12-17) with NEDDISH, Schneeberger et al. (2020) identified homozygous or compound heterozygous mutations in the MADD gene (see, e.g., 603584.0004 and 603584.0009). The families were of various ethnic descents, including Persian and Caucasian, and the patients were ascertained through international collaboration. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Most were absent from the gnomAD database, but 1 was present at a low frequency. Missense, nonsense, and frameshift mutations were identified. In vitro functional expression studies of fibroblasts derived from 1 patient (patient 18) showed disruption of several MADD functions compared to controls (see 603584.0009), consistent with a loss-of-function or hypomorphic effect.