Clinical characteristics.

EMC10-related neurodevelopmental disorder (EMC10-NDD) is characterized by moderate-to-severe developmental delay and mild-to-severe intellectual disability. Seizures, speech delay, poor weight gain, and growth deficiency are common in individuals with EMC10-NDD. Neurobehavioral manifestations, microcephaly, kidney and urinary tract abnormalities (nephrocalcinosis, renal cysts, and hydronephrosis), and upper limb anomalies (cubitus valgus, arachnodactyly, and bilateral fifth digit clinodactyly) have been reported in a few individuals.

Diagnosis/testing.

The diagnosis of EMC10-NDD is established in a proband by identification of biallelic pathogenic variants in EMC10 on molecular genetic testing.

Management.

Treatment of manifestations: Developmental and educational support; standard treatments for behavioral manifestations, epilepsy, and renal manifestations; nutritional support for poor weight gain; social work and family support as needed.

Surveillance: Assessment of developmental progress and educational needs, musculoskeletal manifestations, behavioral issues, new seizures or changes in seizures, growth, nutrition, and family needs at each visit. Follow-up labs and imaging for kidney function, nephrocalcinosis, and renal cysts as recommended by nephrologist.

Genetic counseling.

EMC10-NDD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an EMC10 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the EMC10 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

EMC10-related neurodevelopmental disorder (EMC10-NDD) should be considered in probands with the following clinical and imaging findings and family history:

Clinical findings

• Moderate-to-severe developmental delay
• Mild-to-severe intellectual disability
• Behavioral abnormalities and impaired social skills
• Seizures: multifocal, generalized tonic–clonic, and/or febrile
• Poor weight gain and growth deficiency
• Microcephaly (in some individuals)
• Upper limb anomalies: cubitus valgus, arachnodactyly, and fifth finger clinodactyly

Renal imaging findings. Medullary nephrocalcinosis, renal cysts, and hydronephrosis (in some individuals)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of EMC10-NDD is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in EMC10 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic, and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic EMC10 variants of uncertain significance (or of one known EMC10 pathogenic variant and one EMC10 variant of uncertain significance) does not establish or rule out the diagnosis.

Because the phenotype of EMC10-NDD is indistinguishable from many other neurodevelopmental disorders, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of EMC10, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability (ID) multigene panel that includes EMC10 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used and yields results similar to an ID multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing ID, whereas some multigene panels may not. Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

EMC10-related neurodevelopmental disorder (EMC10-NDD) is characterized by developmental delay, intellectual disability, and dysmorphic features (long face, pointed chin, nystagmus, crowded teeth). Neurobehavioral manifestations, seizures, growth deficiency, and microcephaly have been reported in some individuals. To date, 30 individuals have been identified with biallelic pathogenic variants in EMC10 [Umair et al 2020, Shao et al 2021, Haddad-Eid et al 2022, Kaiyrzhanov et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay. Most individuals with EMC10-NDD present with developmental delay affecting motor, speech, and cognition. Developmental delays are variable, with disability ranging from moderate to severe. Most affected individuals can walk with or without support, while a few are nonambulatory (3/30). Speech delay was reported in 14 of 30 individuals. Most individuals acquire words or short sentences with speech therapy support, but a significant proportion remain nonverbal and rely on other means of communication.

Intellectual disability. Most individuals with EMC10-NDD present with intellectual disability ranging from mild to severe.

Neurobehavioral manifestations. Some individuals have behavioral findings including attention-deficit/hyperactivity disorder, shyness, and impaired social skills.

Epilepsy. The onset of seizures ranges from the neonatal period to childhood. Reported seizure types include subclinical tonic seizures, febrile seizures, multifocal seizures, and generalized tonic-clonic seizures. Seizures have been treated with sodium valproate and carbamazepine. EEG in one affected individual revealed bilateral frontotemporal epileptogenic dysfunction.

Growth deficiency. Most affected individuals had prenatal and postnatal growth deficiency. Although poor weight gain has been reported, feeding issues have not been reported in individuals with EMC10-NDD. Microcephaly was reported in four of 25 individuals; however, head circumference was not documented in all of these reports. Congenital microcephaly has been reported. In one individual head circumference was reported to be one standard deviation (SD) below the mean; in a second individual, head circumference was two SDs below the mean. Severe microcephaly has not been reported.

Craniofacial features. Variable dysmorphic facial features have been observed in all affected individuals reported to date, including a long, triangular face, tall forehead, bifrontal narrowing, thick eyebrows, narrow nasal bridge, low columella, short philtrum, and pointed chin.

Kidney and urinary tract abnormalities included nephrocalcinosis (4/30 individuals), renal cysts (5/30), and mild hydronephrosis or hydroureter (3/30). One individual had end-stage kidney disease that required kidney transplantation. To date, the outcome following kidney transplant has not been reported.

Upper limb anomalies observed in some affected individuals include cubitus valgus, arachnodactyly, and bilateral fifth digit clinodactyly.

Neuroimaging. Most affected individuals have abnormal brain MRI findings of variable severity including Chiari I malformation or ectopia, thin corpus callosum, myelination abnormalities, and white matter abnormalities.

Prognosis. It is unknown whether life span in individuals with EMC10-NDD is decreased. One reported individual is alive at age 27 years [Shao et al 2021], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

The prevalence of this rare genetic disorder is unknown. To date, the clinical phenotype in 30 individuals from 15 different families has been reported [Umair et al 2020, Shao et al 2021, Haddad-Eid et al 2022, Kaiyrzhanov et al 2022]. Most affected individuals with EMC10-NDD are from Saudi Arabia (six affected individuals from four families) [Umair et al 2020, Shao et al 2021].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EMC10-NDD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

EMC10-related neurodevelopmental disorder (EMC10-NDD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an EMC10 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EMC10 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an EMC10 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with EMC10-NDD are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an EMC10 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the EMC10 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• EMC10 molecular genetic testing for the reproductive partners of known carriers should be considered, particularly if consanguinity is likely.

Prenatal Testing and Preimplantation Genetic Testing

Once the EMC10 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The endoplasmic reticulum membrane protein complex (EMC) protein family was first identified in yeast as a multiprotein transmembrane complex composed of ten subunits, where it was thought to be responsible for eliminating misfolded membrane proteins [Jonikas et al 2009]. The EMC may facilitate interactions between mitochondria and the endoplasmic reticulum, thus modulating the processing and folding of different proteins [Lahiri et al 2014]. It also plays a key role in the stability of different transmembrane proteins, such as rhodopsin, which has been reported to cause retinal degeneration in Drosophila [Xiong et al 2020].

In an in vitro study, endoplasmic reticulum membrane protein complex subunit 10 (EMC10) was suggested as a potential therapeutic target for malignant glioblastoma after being found to exert cell proliferation inhibition, invasion, angiogenesis in endothelial cells, and cell migration in glioma cell lines [Junes-Gill et al 2014]. In schizophrenia mouse models, reduced Mirta22 (human EMC10 ortholog) levels completely rescued the dendritic deficits and spine formation at the hippocampal pyramidal neurons, thus suggesting a key role in neuronal dendrites and spine development [Xu et al 2013]. Furthermore, studies revealed that Emc10 knockout mice (Emc10^−/−) showed abnormal behavior (hyperactivity, abnormal vocalization), abnormal gait, decreased bone mineral content, persistence of hyaloid vascular system, cardiovascular issues (decreased heart rate), deceased corpuscular volume in females, thrombocytopenia, metabolic effects, and infertility phenotypes in males (MGI: 5548589) [Zhou et al 2018].

Mechanism of disease causation. Loss of function

Author Notes

Dr Muhammad Umair (as.dem.ahgn@umriamu) and Professor Majid Alfadhel (as.dem.ahgnm@amlehdaf) are actively involved in clinical research regarding individuals with EMC10-related neurodevelopmental disorder (EMC10-NDD). They would be happy to communicate with persons who have any questions regarding the diagnosis of EMC10-NDD or other considerations.

Contact Dr Muhammad Umair (as.dem.ahgn@umriamu) and Professor Majid Alfadhel (as.dem.ahgnm@amlehdaf) to inquire about review of EMC10 variants of uncertain significance.

Dr Muhammad Umair (as.dem.ahgn@umriamu) and Professor Majid Alfadhel (as.dem.ahgnm@amlehdaf) are also interested in hearing from clinicians treating families affected by rare neurodevelopmental disorders in whom no causative variant has been identified through molecular genetic testing.

Acknowledgments

We would like to thank the patients, families, and clinicians who have participated in our previous publications delineating this condition.

We are grateful to the King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard Health Affairs (MNGHA), Kingdom of Saudi Arabia (KSA).

Revision History

• 15 June 2023 (sw) Review posted live
• 15 February 2023 (mu) Original submission

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