ORPHA: 528084; DO: 0070417;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p11.2 | Neurodevelopmental disorder with speech impairment and dysmorphic facies | 619056 | Autosomal dominant | 3 | SETD1A | 611052 |
A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID) is caused by heterozygous mutation in the SETD1A gene (611052) on chromosome 16p11.
Neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID) is characterized by developmental delay associated with mild to moderately impaired intellectual development or learning difficulties, behavioral or psychiatric abnormalities, and delayed speech and language acquisition. Additional features include dysmorphic facies, distal limb anomalies, gastrointestinal problems or feeding difficulties, and hypotonia. The phenotypic features and severity of the disorder are variable (summary by Kummeling et al., 2021).
Kummeling et al. (2021) reported 15 unrelated patients with a similar neurodevelopmental disorder who were ascertained from several different clinical or research centers through the GeneMatcher program. Twelve patients were between 34 months and 10 years of age, 2 were in their teens, and 1 was 23 years old. One boy (patient 5) died at 4 years of age. The patients had global developmental delay with mild motor delay, mild to moderately impaired intellectual development, learning difficulties, and poor speech and language acquisition. One girl (patient 14) was specifically noted to have speech apraxia. Most had behavioral or psychiatric abnormalities, including aggressive behavior, short attention span, anxiety, sleep disturbances, overfriendliness, and autistic features. Two older patients had features of a psychotic disorder. All patients had dysmorphic facial features, although the features were somewhat variable. Common findings included high forehead, downslanting palpebral fissures, epicanthal folds, deep-set eyes, wide nose with anteverted nares and broad tip, full cheeks, low-set ears, microtia, full cheeks, everted upper lip, wide mouth, and widely spaced teeth. Many patients also had distal limb anomalies, such as pes planus, broad fingers, or long tapered fingers; joint hypermobility was often present. Additional features present in some patients included gastrointestinal problems, recurrent infections, skin abnormalities, visual impairment, and hypotonia. Three patients had seizures and 4 had nonspecific findings on brain imaging, such as abnormal corpus callosum or white matter abnormalities.
Clinical Variability
Eising et al. (2019) reported a 6-year-old girl (patient 04) who presented with speech delay and childhood apraxia of speech (CAS). Clinical details were limited, but she was noted to have poor oral and listening skills, dysarthria, and motor impairment. IQ was in the average range. Genetic analysis identified a de novo heterozygous frameshift mutation in the SETD1A gene: functional studies of the variant were not performed. The patient was part of a cohort of 19 probands diagnosed with CAS who underwent genetic studies.
The heterozygous mutations in the SETD1A gene that were identified in patients with NEDSID by Kummeling et al. (2021) occurred de novo.
In 15 unrelated patients with NEDSID, Kummeling et al. (2021) identified 14 different de novo heterozygous mutations in the SETD1A gene (see, e.g., 611052.0001; 611052.0006-611052.0008). The mutations were found by routine diagnostic testing and the patients were ascertained from several different places through the GeneMatcher program. There were 5 nonsense, 6 frameshift, 1 missense, and 2 splice site mutations. All variants were predicted to disrupt or delete the SET catalytic domain. Five patients carried additional variants of uncertain significance affecting other genes. Analysis of fibroblasts derived from 3 patients, including the patient with the only SETD1A missense variant (Y1499D; 611052.0006), showed elevated activation of the DNA damage response and increased DNA degradation under stress conditions compared to controls. These data indicated that the mutations likely caused a loss-of-function effect and SETD1A haploinsufficiency. Kummeling et al. (2021) concluded that the findings were consistent with a possible role of H3K4 methylation and other epigenetic changes in regulating the function of adult neurons post development.
Singh et al. (2016) reported 7 patients with schizophrenia (SCZD; 181500) and learning difficulties who had heterozygous loss-of-function variants in the SETD1A gene (see, e.g., 611052.0001). The mutations were found to occur de novo when parental DNA was available. No loss-of-function variants were found in controls (p = 3.3 x 10 (-9)). The patients were part of a cohort of 4,264 patients with schizophrenia, 9,343 controls, and 1,077 trios who underwent genetic studies. Including 3 previously reported patients (Takata et al., 2014; Guipponi et al., 2014), 7 of 10 individuals with schizophrenia reported by Singh et al. (2016) who carried SETD1A variants also had learning difficulties. Metaanalysis results showed that SETD1A disruptions are rare in schizophrenia, occurring in about 0.13% of cases. Singh et al. (2016) also found heterozygous loss-of-function variants in the SETD1A gene in 4 of 4,281 children with severe neurodevelopmental disorders and in 2 individuals from a sample of 5,720 Finnish exomes, both of whom had neuropsychiatric phenotypes. The findings suggested that loss-of-function variants in the SETD1A gene can cause a range of neurodevelopmental disorders, and that epigenetic dysregulation of the histone H3K4 methylation pathway may play a role in the pathogenesis of schizophrenia.
Kummeling et al. (2021) found that knockdown of the Drosophila SETD1A ortholog Set1 in terminally differentiated postmitotic neurons of the mushroom body (MB), the primary memory and learning center of the fly brain, resulted in memory deficits as assessed by the courtship conditioning assay. Histologic studies of mutant fly brains did not show morphologic abnormalities in the MB. The authors concluded that this gene is required for normal functioning of adult MB neurons during memory formation, rather than during development.
Eising, E., Carrion-Castillo, A., Vino, A., Strand, E. A., Jakielski, K. J., Scerri, T. S., Hildebrand, M. S., Webster, R., Ma, A., Mazoyer, B., Francks, C., Bahlo, M., Scheffer, I. E., Morgan, A. T., Shriberg, L. D., Fisher, S. E. A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development. Molec. Psychiat. 24: 1065-1078, 2019. [PubMed: 29463886] [Full Text: https://doi.org/10.1038/s41380-018-0020-x]
Guipponi, M., Santoni, F. A., Setola, V., Gehrig, C., Rotharmel, M., Cuenca, M., Guillin, O., Dikeos, D., Georgantopoulos, G., Papadimitrou, G., Curtis, L., Meary, A., and 9 others. Exome sequencing in 53 sporadic cases of schizophrenia identified 18 putative candidate genes. PLoS One 9: e112745, 2014. Note: Electronic Article. Erratum: PLoS One: 10: e0141630, 2015. [PubMed: 25420024] [Full Text: https://doi.org/10.1371/journal.pone.0112745]
Kummeling, J., Stremmelaar, D. E., Raun, N., Reijnders, M. R. F., Willemsen, M. H., Ruiterkamp-Versteeg, M., Schepens, M., Man, C. C. O., Gilissen, C., Cho, M. T., McWalter, K., Sinnema, M., and 31 others. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome. Molec. Psychiat. 26: 2013-2024, 2021. [PubMed: 32346159] [Full Text: https://doi.org/10.1038/s41380-020-0725-5]
Singh, T., Kurki, M. I., Curtis, D., Purcell, S. M., Crooks, L., McRae, J., Suvisaari, J., Chheda, H., Blackwood, D., Breen, G., Pietilainen, O., Gerety, S. S., and 51 others. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nature Neurosci. 19: 571-577, 2016. [PubMed: 26974950] [Full Text: https://doi.org/10.1038/nn.4267]
Takata, A., Xu, B., Ionita-Laza, I., Roos, J. L., Gogos, J. A., Karayiorgou, M. Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. Neuron 82: 773-780, 2014. [PubMed: 24853937] [Full Text: https://doi.org/10.1016/j.neuron.2014.04.043]