Other entities represented in this entry:
ORPHA: 178469; DO: 0070041;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q11.23 | ?Intellectual developmental disorder, autosomal dominant 11 | 614257 | Autosomal dominant | 3 | EPB41L1 | 602879 |
A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome on chromosome 20q11-q12. One patient with autosomal dominant intellectual development disorder-11 (MRD11) has been found to have a mutation in the EPB41L1 gene on chromosome 20q11.
Chromosome 20q11-q12 deletion syndrome is characterized by global developmental delay, poor overall growth, sometimes with severe feeding difficulties, facial dysmorphism, and distal skeletal anomalies. Some patients may have hearing impairment, retinopathy, or cardiac defects. It is a multisystemic disorder with variable features (summary by Loddo et al., 2018).
Chromosome 20q11-q12 Deletion Syndrome
Callier et al. (2006) reported a 4-year-old girl with intrauterine growth retardation, severe feeding difficulties requiring enteral feeding, hypertonia, and global developmental delay. She walked at age 30 months, but was nonverbal and showed behavioral abnormalities, including aggression, stereotypies, and head-banging. Facial dysmorphic features included a triangular face with large forehead and frontal bossing, plagiocephaly, downslanting palpebral fissures, hypertelorism, strabismus, thin nose with hypoplastic alae nasi and long columella, low-set ears, well-defined philtrum, thin lips, and microretrognathia. Other features included dry skin, fifth finger clinodactyly, and low-implanted large toes. Brain imaging showed cortical atrophy.
Posmyk et al. (2014) reported a 2-year-old Polish girl with 20q11 deletion syndrome. She had pre- and post-natal growth retardation, severe feeding problems necessitating tube feeding, hypotonia, and respiratory distress. She also had cleft palate, patent foramen ovale, hypertrophic cardiomyopathy, unilateral preaxial polydactyly, gastroesophageal reflux, and peripheral hypertonia. Craniofacial features noted in infancy included microcephaly, sloping forehead, round face, arched eyebrows, narrow palpebral fissures, widely spaced eyes, wide and prominent nasal bridge, long nasal ridge, broad nasal tip, microretrognathia, deep chin groove, and low-set abnormal ears. Ophthalmologic examination showed strabismus, astigmatism, hyperopia, and retinal pigmentary abnormalities. By age 12 months, the face became triangular with high forehead and sparse hair. She had epicanthal folds, long and prominent philtrum, thin lips, and protruding ears. She had severely impaired intellectual development with poor language and inability to walk independently.
Jedraszak et al. (2015) reported 6 unrelated patients, ranging in age from 2 months to 20 years, with global developmental delay, dysmorphic facial features, and distal skeletal anomalies associated with de novo heterozygous interstitial deletions on chromosome 20q11.2. Five patients had neonatal feeding difficulties, and 2 patients each had intrauterine growth retardation, cardiac defects, ocular anomalies, hearing impairment, and abnormal brain imaging, such as cortical atrophy or delayed myelination. Dysmorphic facial features changed somewhat with time: at first, patients tended to show microretrognathia with short philtrum, but later both disappeared and the patients developed midface hypoplasia, high forehead, frontal bossing, deep-set eyes, and hypertelorism. Other features included ear hypoplastic alae nasi, long columella, and abnormal ears. The patients had variable distal skeletal defects, such as brachydactyly, clinodactyly, camptodactyly, talus valgus, and adducted thumbs. The patients had variably impaired intellectual development with poor speech and language. A few patients were able to attend special schools but had difficulties; at least 1 patient had autism spectrum disorder.
Loddo et al. (2018) reported a 5-year-old girl with 20q11-q12 deletion syndrome. She had poor growth with microcephaly, mild developmental delay with poor speech, and submucosal cleft palate that was surgically repaired. Dysmorphic features included flat face, high forehead, arched eyebrows, deep-set eyes, hypertelorism, epicanthal folds, wide nasal base with underdeveloped alae nasi, thin upper lip, and prognathism. She also had distal skeletal anomalies of the hands and feet, namely brachydactyly and clinodactyly.
Intellectual Developmental Disorder, Autosomal Dominant 11
Hamdan et al. (2011) reported a 6-year-old boy with hypotonia and severely impaired intellectual development. He did not have seizures; brain imaging was normal.
Callier et al. (2006) identified a de novo heterozygous 6.6-Mb interstitial deletion on chromosome 20q11.22-q11.23 in a 4-year-old girl with developmental delay, severe feeding difficulties, and dysmorphic features. The deleted region included at least 88 genes.
In a 2-year-old Polish girl with developmental delay and dysmorphic features, Posmyk et al. (2014) identified a de novo heterozygous 5.9-Mb interstitial deletion on chromosome 20q11.21-q11.23. The deleted region contained 87 known genes.
In 6 unrelated patients with a similar neurodevelopmental disorder, Jedraszak et al. (2015) used array CGH to identify de novo heterozygous deletions of chromosome 20q11.2, with sizes ranging from 2.24 Mb to 7.7 Mb. The minimal critical region could be narrowed to 1.62 Mb. The authors suggested that the loss of 3 genes, EPB41L1 (602879), SAMHD1 (606754), and GDF5 (601146), may be responsible for certain phenotypic aspects. However, the deletion in patient 5 did not include EPB41L1 or SAMHD1, and the deletion in patient 6 did not include GDF5. The authors noted that patient 5 had a somewhat milder phenotype.
In a 5-year-old girl with developmental delay and dysmorphic features, Loddo et al. (2018) identified low-level mosaicism for a 7.5-Mb deletion on chromosome 20q11.2-q12, including the 1.6-Mb critical region identified by Jedraszak et al. (2015). The deletion in this patient involved 72 genes. The authors suggested that loss of GDF5 may contribute to the skeletal anomalies and that loss of EPB41L1 may contribute to the neurologic features. Involvement of GHRH (139190) was also postulated, possibly contributing to growth retardation.
The heterozygous deletions of chromosome 20q11.2 that were identified in patients with a similar neurodevelopmental disorder by Jedraszak et al. (2015) occurred de novo.
The heterozygous mutation in the EPB41L1 gene that was identified in a patient with MRD11 by Hamdan et al. (2011) occurred de novo.
In a patient with intellectual developmental disorder 11, Hamdan et al. (2011) identified a de novo heterozygous missense mutation in the EPB41L1 gene (P854S; 602879.0001) on chromosome 20q11.2-q12. The mutation affects a highly conserved proline in the C-terminal domain of the 4.1N protein, which binds AMPA receptor subunits. Coimmunoprecipitation studies showed that the proline-to-serine substitution at codon 854 reduces the binding of 4.1N to GLUR1 (138248) by 50% in HEK293 cells. Moreover, insertion of GLUR1 at the synaptic membrane was significantly decreased in transfected hippocampal neurons producing mutant 4.1N when compared to cells producing wildtype 4.1N. The patient was part of a cohort of 95 sporadic cases of nonsyndromic intellectual disability who underwent sequencing of a targeted panel of genes involved in glutamate receptor function.
Callier, P., Faivre, L., Marle, N., Thauvin-Robinet, C., Sanlaville, D., Gosset, P., Prieur, M., Labenne, M., Huet, F., Mugneret, F. Major feeding difficulties in the first reported case of interstitial 20q11.22-q12 microdeletion and molecular cytogenetic characterization. Am. J. Med. Genet. 140A: 1859-1863, 2006. [PubMed: 16892304] [Full Text: https://doi.org/10.1002/ajmg.a.31395]
Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., Park, A.-R., Spiegelman, D., Dobrzeniecka, S., Piton, A., Tomitori, H., Daoud, H., and 22 others. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am. J. Hum. Genet. 88: 306-316, 2011. Note; Erratum: Am. J. Hum. Genet. 88: 516 only, 2011. [PubMed: 21376300] [Full Text: https://doi.org/10.1016/j.ajhg.2011.02.001]
Jedraszak, G., Demeer, B., Mathieu-Dramard, M., Andrieux, J., Receveur, A., Weber, A., Maye, U., Foulds, N., Temple, I. K., Crolla, J., Alex-Cordier, M.-P., Sanlaville, D., Ewans, L., Wilson, M., Armstrong, R., Clarkson, A., Copin, H., Morin, G. Clinical and molecular characterization of the 20q11.2 microdeletion syndrome: six new patients. Am. J. Med. Genet. 167A: 504-511, 2015. [PubMed: 25572454] [Full Text: https://doi.org/10.1002/ajmg.a.36882]
Loddo, S., Alesi, V., Genovese, S., Orlando, V., Calacci, C., Restaldi, F., Pompili, D., Liambo, M. T., Digilio, M. C., Dallapiccola, B., Dentici, M. L., Novelli, A. First report of low-rate mosaicism for 20q11.21q12 deletion and delineation of the associated disorder. Cytogenet. Genome Res. 156: 87-94, 2018. [PubMed: 30372694] [Full Text: https://doi.org/10.1159/000493935]
Posmyk, R., Lesniewicz, R., Gogiel, M., Chorazy, M., Bakunowicz, A., Sielicka, D., Vermeesch, J., Nowakowska, B. A. The smallest de novo deletion of 20q11.21-q11.23 in a girl with feeding problems, retinal dysplasia, and skeletal abnormalities. Am. J. Med. Genet. 164A: 1056-1061, 2014. [PubMed: 24459047] [Full Text: https://doi.org/10.1002/ajmg.a.36394]