A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-85 with or without midline brain defects (DEE85) is caused by heterozygous mutation in the SMC1A gene (300040) on chromosome Xp11.

Mutation in the SMC1A gene can also cause Cornelia de Lange syndrome-2 (CDLS2; 300590), a milder disorder with some overlapping features.

Developmental and epileptic encephalopathy-85 with or without midline brain defects (DEE85) is an X-linked neurologic disorder characterized by onset of severe refractory seizures in the first year of life, global developmental delay with impaired intellectual development and poor or absent speech, and dysmorphic facial features. The seizures tend to show a cyclic pattern with clustering. Many patients have midline brain defects on brain imaging, including thin corpus callosum and/or variable forms of holoprosencephaly (HPE). The severity and clinical manifestations are variable. Almost all reported patients are females with de novo mutations predicted to result in a loss of function (LOF). However, some patients may show skewed X inactivation, and the pathogenic mechanism may be due to a dominant-negative effect. The SMC1A protein is part of the multiprotein cohesin complex involved in chromatid cohesion during DNA replication and transcriptional regulation; DEE85 can thus be classified as a 'cohesinopathy' (summary by Symonds et al., 2017 and Kruszka et al., 2019).

For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Hansen et al. (2013) reported an 11-year-old Swiss girl with DEE85. She was born with microcephaly, congenital hip dysplasia, and diaphragmatic hernia. At age 3 months, she developed generalized tonic-clonic seizures associated with EEG abnormalities; the seizures tended to occur in clusters. She had global developmental delay with mildly delayed walking and mild speech delay. Dysmorphic features included a round face with arched eyebrows, short nose, upslanting palpebral fissures, smooth philtrum, mild retrognathia, crowded teeth, flattened midface, clinodactyly, and camptodactyly. The authors noted that the report expanded the phenotypic spectrum associated with SMC1A mutations.

Lebrun et al. (2015) reported a 7-year-old girl, born of unrelated Portuguese parents, with DEE85. She had intrauterine growth retardation and manifested microcephaly and mild dysmorphic facial features at birth. She had synophrys, thin nose and upper lip, retrognathia, triangular face, and small hands and feet. During the first month of life, she developed refractory focal seizures, infantile spasms, and multifocal seizures associated with hypsarrhythmia on EEG. Thereafter she showed severe developmental delay with poor visual contact, impaired intellectual development, absent speech, axial hypotonia, peripheral hypertonia, spastic tetraparesis, scoliosis, and poor overall growth. Other features included gastroesophageal reflux and stereotypic hand movements. Brain imaging showed small frontal lobes and thin corpus callosum.

Goldstein et al. (2015) reported 2 unrelated girls with DEE85. Patient A was a 4-year-old girl with intractable epilepsy associated with status epilepticus, global developmental delay, severe hypotonia, limb hyperreflexia, and microcephaly. She was able to walk a few steps at age 18 months, but later regressed and was nonambulatory. She was nonverbal and had a feeding tube. Her seizures were refractory to medication and evolved into clusters with a cyclic frequency every 1 to 2 weeks. Other features included long eyelashes, short nose, hirsutism, and small hands and feet. Brain imaging showed nonspecific findings, including mildly enlarged ventricles, mildly rotated hippocampal heads, and some white matter hyperintensities. Patient B was a 3-year-old girl who had mild developmental delay before the onset of seizures at 11 months of age. The seizures were initially refractory, but eventually were controlled. Brain imaging showed mild enlargement of extraaxial spaces and slight thinning of the corpus callosum. Neither patient showed classic dysmorphic features suggestive of CDLS, thus expanding the phenotypic spectrum.

Jansen et al. (2016) reported 2 unrelated female patients with DEE85. Patient 1 was a 46-year-old woman with severe developmental delay apparent from infancy. She had impaired intellectual development with absent language and inability to crawl or walk. At age 9 months, she developed refractory seizures associated with EEG abnormalities. She also had a history of cleft palate. Physical examination as an adult showed small head circumference (-2.5 SD), short stature, low anterior hairline, flat midface, straight eyebrows with deep-set eyes, long small ears, long nose, short philtrum, disorganized dentition, small hand with tapering fingers, and contractures of the fingers and toes. Other features included axial hypotonia, peripheral spasticity, visual impairment, myopia, and scoliosis. Brain imaging showed enlarged ventricles and cerebellar hypoplasia. The other patient was a 14-year-old girl who developed refractory generalized seizures at 2 months of age. She had global developmental delay with loss of ambulation in childhood, severely impaired intellectual development with absent speech, hypotonia, poor feeding requiring a G-tube, and poor overall growth with small head circumference (-2.5 SD). Dysmorphic features included trigonocephaly, upslanting palpebral fissures, blepharophimosis, posteriorly rotated ears, full cheeks, full lips, short philtrum gingival hyperplasia, and small hands with slender fingers. Jansen et al. (2016) concluded that the phenotype in these patients was distinct from CDLS2.

Symonds et al. (2017) reported 10 unrelated girls with early-onset refractory seizures, 8 of whom were probands identified through the DDD cohort based on exome sequencing. A ninth patient was a sister of one of the 8 probands, and a tenth patient was identified through analysis of a custom gene panel. All presented with drug-resistant epilepsy within the first months of life (median, 4.5 months), although 2 patients eventually became seizure-free. Seizure types were variable, including afebrile motor seizures, tonic-clonic, clonic, focal, myoclonic, absence, and generalized. EEG showed focal or multifocal abnormalities, spike and sharp-wave complexes, and generalized background slowing; some patients had status epilepticus. The seizures tended to occur in clusters in a cyclic pattern. The patients had moderate to profound developmental delay with delayed walking or inability to walk, impaired intellectual development and absent language, hypotonia, and poor growth with short stature and progressive microcephaly. Four patients had congenital cardiac anomalies, mainly septal defects, 2 had cleft palate, and 2 had bifid thoracic vertebrae. Dysmorphic features included flattened midface, short upturned nose, and shallow philtrum. Brain imaging was normal in 5 patients and showed nonspecific anomalies in 2, whereas 3 had variable midline brain defects, including small cavum septum vergae, thin corpus callosum, and semilobar holoprosencephaly, respectively. Of 2 affected sisters, one (patient 9) had semilobar HPE and died at 11 months of age; the other (patient 8), who carried the same mutation, had no structural organ anomalies, no dysmorphic features, and normal brain MRI. None of the patients were considered clinically to have features of CDLS before the genetic analysis, and the authors suggested that the phenotype was not only distinct from, but also more severe than CDLS.

Patients with Significant Midline Brain Defects

Kruszka et al. (2019) reported 5 unrelated girls (patients 7-11), ranging in age from 15 months to 6 years, with early-onset epileptic encephalopathy and midline brain defects. The patients were ascertained due to holoprosencephaly. Four patients had early-onset seizures; seizures were not reported in a 15-month-old girl. Three patients had semilobar HPE, 1 had triventricular ectasia, and 1 had middle interhemispheric HPE. All had microcephaly, and most had dysmorphic facial features, including brachycephaly, sloping forehead, arched eyebrows, synophrys, midface flattening, bitemporal narrowing, depressed nasal bridge, upslanting palpebral fissures, and single central incisor. Additional common but variable features included growth delay, small hands and feet, and feeding problems. One patient had spina bifida and another had patent foramen ovale.

The heterozygous mutations in the SMC1A gene that were identified in female patients with DEE85 with or without midline brain defects by Goldstein et al. (2015), Jansen et al. (2016), and Kruszka et al. (2019) occurred de novo.

In an 11-year-old Swiss girl with DEE85, Hansen et al. (2013) identified a de novo heterozygous mutation (c.1731G-A, E577E) in the SMC1A gene, predicted to result in a splicing defect. Functional studies of the variant and studies of patient cells were not performed.

In a 7-year-old girl, born of unrelated Portuguese parents, with DEE85, Lebrun et al. (2015) identified a de novo heterozygous splice site mutation in the SMC1A gene (300040.0007). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Analysis of patient fibroblasts showed the presence of only the mutant transcript, which was significantly reduced compared to controls, suggesting nonsense-mediated mRNA decay and a loss of function (LOF).

In 2 unrelated girls with DEE85, Goldstein et al. (2015) identified de novo heterozygous frameshift mutations in the SMC1A gene (300040.0008 and 300040.0009). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. X-inactivation studies in peripheral blood cells showed a skewed pattern (93:7) in 1 patient, but a random pattern in the other. Additional functional studies of the variants and studies of patient cells were not performed.

In 2 unrelated females with DEE85, Jansen et al. (2016) identified de novo heterozygous LOF mutations in the SMC1A gene (see, e.g., 300040.0010). The mutations were found by whole-genome sequencing. X-inactivation studies in 1 patient showed a random pattern, whereas it was skewed in the other patient (85:15); additional functional studies were not performed. Jansen et al. (2016) concluded that the de novo LOF mutations in the SMC1A gene in females cause an abnormal dosage effect and that the resulting phenotype is distinct from CDLS2. The authors further suggested that LOF mutations in males may be embryonic lethal.

In 10 unrelated females with DEE85, Symonds et al. (2017) identified de novo heterozygous nonsense, frameshift, or splice site mutations in the SMC1A gene (see, e.g., 300040.0011-300040.0013). Functional studies of the variants were not performed. X-inactivation studies, performed in some patients, had variable results: some showed a random pattern, whereas others had a skewed pattern. Symonds et al. (2017) speculated that if SMC1A escapes X inactivation, then haploinsufficiency is unlikely to be the causative mechanism; rather, the authors postulated a dominant-negative effect. The findings also suggested that complete SMC1A deficiency is embryonic lethal, as no males with such mutations have been reported.

In 5 unrelated girls (patients 7-11) with DEE85 and variable midline brain defects, including holoprosencephaly (HPE), Kruszka et al. (2019) identified de novo heterozygous mutations in the SMC1A gene (see, e.g., 300040.0014 and 300040.0015). All mutations except 1 were nonsense, frameshift, or splice site mutations, suggesting a loss-of-function effect; there was 1 missense mutation. Functional studies of the variants and studies of patient cells were not performed. Knockdown of the SMC1A gene in human neural progenitor cells resulted in upregulation of GLI2 (165230), ZIC2 (603073), and SMAD3 (603109) gene expression. Although the significance of these findings was unclear, they demonstrated that loss of SMC1A perturbs the expression of genes involved in HPE. The patients were part of a cohort of 277 individuals with HPE as well as gathered through collaborative efforts such as GeneMatcher.