Early onset or syndromic epilepsy
Gene: DMXL2
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
developmental and epileptic encephalopathy 81
The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.Created: 3 Mar 2022, 5:34 p.m. | Last Modified: 3 Mar 2022, 5:34 p.m.
Panel Version: 2.491
The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 3 Mar 2022, 5:34 p.m. | Last Modified: 3 Mar 2022, 5:34 p.m.
Panel Version: 2.491
Comment on mode of inheritance: All cases with epilepsy have been biallelicCreated: 30 Jun 2020, 10:36 a.m. | Last Modified: 30 Jun 2020, 10:36 a.m.
Panel Version: 2.101
Comment on list classification: Promoting to amber for now. There is enough evidence for this gene to be rated GREEN at the next major review.Created: 30 Jun 2020, 10:28 a.m. | Last Modified: 30 Jun 2020, 10:28 a.m.
Panel Version: 2.100
Associated with Epileptic encephalopathy, early infantile, 81 #618663 (AR) in OMIM.
PMID: 31688942 - Esposito et al 2019 - report 3 unrelated families with affected siblings with compound het or homozygous variants in DMXL2 identified by WES. The severe developmental and epileptic encephalopathy manifested from the first day of life and was associated with deafness, mild peripheral polyneuropathy and dysmorphic features.
PMID: 30237576 - Maddirevula et al 2019 - report a case of a child with intellectual disability, epilepsy, macrocephaly, and dysmorphism in which a homozygous truncating variant in DMXL2 was found.Created: 30 Jun 2020, 10:16 a.m. | Last Modified: 30 Jun 2020, 10:16 a.m.
Panel Version: 2.97
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Ohtahara syndrome; Epileptic encephalopathy, early infantile, 81, 618663
Publications
Four unrelated families reported.Created: 22 Jan 2020, 1:28 a.m. | Last Modified: 22 Jan 2020, 1:28 a.m.
Panel Version: 2.0
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Epileptic encephalopathy, early infantile, 81, MIM# 618663
Publications
Variants in this GENE are reported as part of current diagnostic practice
This gene can be considered for inclusion in both ID and epilepsy panels probably with green (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc) or amber rating.
Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited.
DD, ID and (probably) epilepsy appear however to be constant features in several individuals with biallelic pathogenic variants as summarized in the studies below.
OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following:
- Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AR) [based on refs 2,3]
- ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype]
- ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1]
DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1).
This gene is included in some gene panels for ID.
[1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion.
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[2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc).
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[3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes.
All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years.
Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3):
- Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*)
- Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*)
- Fam3 (2 sibs) : homozygosity for c.7518-1G>A
Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605].
In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot.
DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al).
The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ).
As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872).
In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis.
shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation.
The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy.
Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .
Sources: LiteratureCreated: 22 Nov 2019, 7:20 a.m. | Last Modified: 22 Nov 2019, 8:25 a.m.
Panel Version: 1.425
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Epileptic encephalopathy, early infantile, 81, MIM 618663; ?Polyendocrine-polyneuropathy syndrome, MIM 616113
Publications
Tag for-review was removed from gene: DMXL2.
Source NHS GMS was added to DMXL2.
Source Expert Review Green was added to DMXL2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag for-review tag was added to gene: DMXL2.
Mode of inheritance for gene: DMXL2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Gene: dmxl2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: DMXL2 were changed from Epileptic encephalopathy, early infantile, 81, MIM 618663; ?Polyendocrine-polyneuropathy syndrome, MIM 616113 to Epileptic encephalopathy, early infantile, 81, MIM 618663; Ohtahara syndrome
Mode of inheritance for gene: DMXL2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
gene: DMXL2 was added gene: DMXL2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: DMXL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: DMXL2 were set to 25248098; 30237576; 31688942; 30732576 Phenotypes for gene: DMXL2 were set to Epileptic encephalopathy, early infantile, 81, MIM 618663; ?Polyendocrine-polyneuropathy syndrome, MIM 616113 Penetrance for gene: DMXL2 were set to unknown Review for gene: DMXL2 was set to GREEN