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Lenz Microphthalmia Syndrome

, MD
National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland

Initial Posting: ; Last Update: October 2, 2014.

Summary

Disease characteristics. Lenz microphthalmia syndrome (LMS) is characterized by unilateral or bilateral microphthalmia and/or clinical anophthalmia with malformations of the ears, teeth, fingers, skeleton, and/or genitourinary system. Microphthalmia is often accompanied by microcornea and glaucoma. Coloboma is present in approximately 60% of microphthalmic eyes with severity ranging from isolated iris coloboma to coloboma of the ciliary body, choroid, and optic disk. Ears may be low set, anteverted, posteriorly rotated, simple, cup shaped, or abnormally modeled. Hearing loss has been observed. Dental findings include irregularly shaped, missing, or widely spaced teeth. Duplicated thumbs, syndactyly, clinodactyly, camptodactyly, and microcephaly are common, as are narrow/sloping shoulders, underdeveloped clavicles, kyphoscoliosis, exaggerated lumbar lordosis, long cylindric thorax, and webbed neck. Genitourinary anomalies include hypospadias, cryptorchidism, renal hypoplasia/aplasia, and hydroureter. Approximately 60% of affected males have mild-to-severe intellectual disability or developmental delay.

Diagnosis/testing. The diagnosis of Lenz microphthalmia syndrome is based on clinical findings. Mild simple microphthalmia can be identified by measuring the axial length of the globe with A-scan ultrasonography. NAA10 (MCOPS1 locus) and BCOR (MCOPS2 locus) are the only genes known to be associated with Lenz microphthalmia syndrome (LMS).

Management. Treatment of manifestations: For clinical anophthalmos or extreme microphthalmos: regular evaluation by an ocularist for placement of serial enlarging orbital expanders, physical and occupational therapy, special education, and referral to services for the blind. For hearing loss and sleep disorders: treatment dependent on the specific defect and similar to that used in the general population. Institute regular dental examinations and cleaning should be instituted, especially when cognitive developmental delay is present; dental treatment as for the general population.

Surveillance: Annual ophthalmologic examination for those with residual vision, monitoring of renal function, developmental assessments, and lifelong case management to help affected individuals gain access to social services and assistive devices for the blind.

Genetic counseling. Lenz microphthalmia syndrome is inherited in an X-linked manner. The risk to sibs depends on the carrier status of the mother. If the mother is a carrier, the chance of transmitting the pathogenic variant is 50% in each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. The majority of males with Lenz microphthalmia syndrome do not reproduce. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible for families in which the pathogenic variant has been identified in an affected family member. Prenatal ultrasound examination at 18 weeks' gestation can be offered for pregnancies at increased risk to evaluate fetal renal development.

Diagnosis

Suggestive Findings

Lenz microphthalmia syndrome (LMS) should be suspected in males with a combination of the following clinical findings:

  • Ocular malformation. Unilateral or bilateral microphthalmia and/or anophthalmia that may be symmetric or asymmetric:
    • Anophthalmia refers to the histologic diagnosis of complete absence of the globe in the presence of ocular adnexae (eyelids, conjunctiva, and lacrimal apparatus). CT or MRI scan of the orbit shows absence of ocular tissue, optic nerve, and extraocular muscles.
      Note: The term "clinical anophthalmia" should be used for severe microphthalmia when the globe is not detectable on physical examination.
    • "Simple microphthalmia" or "pure microphthalmia" describes a globe that is reduced in total axial length (TAL), has all structural elements intact, and retains some vision. Mild simple microphthalmia can be identified by measuring the axial length of the globe with A-scan ultrasonography. Total axial length of the neonatal eye is normally near 17 mm; an age-adjusted total axial length below the fifth centile defines microphthalmia. The mean total axial length of the adult eye is 23.8 mm; a total axial length of less than 18.5 mm defines microphthalmia.
    • Coloboma is present in approximately 60% of microphthalmic eyes [Ng et al 2002], with severity ranging from isolated iris coloboma to coloboma of the ciliary body, choroid, and optic disk.
    • Congenital cystic eye has not been observed in LMS.
  • Extraocular malformations that vary within and among families:
    • Hypospadias, cryptorchidism, renal aplasia/hypoplasia, hydroureter (77% of individuals)
    • Simple, anteverted, abnormally modeled ears (63%)
    • Abnormal shape of incisors, irregularly spaced teeth (48%)
    • Duplicated thumbs, syndactyly, clinodactyly, camptodactyly (44%)
    • Microcephaly (37%)
    • Narrow/sloping shoulders, underdeveloped clavicles, kyphoscoliosis, exaggerated lumbar lordosis, long cylindrical thorax, webbed neck (26%)
    • Cleft lip/palate (7%)
  • Intellectual disability ranging from mild to severe (63%)
  • Family history consistent with X-linked recessive inheritance

Establishing the Diagnosis

The diagnosis of LMS is established in a proband with identification of a pathogenic variant in one of two known genes, BCOR or NAA10 (see Table 1).

One genetic testing strategy is serial single gene molecular genetic testing of BCOR and NAA10.

An alternative genetic testing strategy is use of a multi-gene panel that includes BCOR, NAA10 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Genomic testing. If single gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of LMS, genomic testing may be considered. Such testing may include whole-exome sequencing (WES) and whole-genome sequencing (WGS).

Notes regarding WES and WGS. (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single gene testing or multi-gene molecular genetic testing panels; (2) most laboratories confirm positive results using a second, well-established method; (3) nucleotide repeat expansions and epigenetic alterations cannot be detected; (4) deletions/duplications larger than 8-10 nucleotides are not detected effectively [Biesecker & Green 2014; full text].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Lenz Microphthalmia Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
Affected MalesCarrier Females
BCORTargeted sequence analysis for c.254C>T 2, 3Unknown 3Unknown 3
NAA10Sequence analysis 4Unknown 5Unknown 5
Deletion/duplication analysis 6UnknownUnknown
Unknown 7NA

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Pathogenic variants included in a panel may vary by laboratory.

3. A missense mutation, c.254C>T, resulting in a change of amino acid at position 85 from proline to leucine (p.Pro85Leu) in BCOR, was found in affected males of the family used to map the MOCPS2 locus [Ng et al 2002, Ng et al 2004], in a white male reported by Hilton et al [2009], and in two Japanese families reported by Suzumori et al [2013]. The low frequency of BCOR pathogenic variants does not allow determination of the mutation detection frequency.

4. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. c.471+2T>A, a splice mutation that may lead to aberrant splicing of exons 7 and 8 of NAA10, has been reported in three affected males with the LMS phenotype that mapped to the MCOPS1 locus [Forrester et al 2001, Esmailpour et al 2014]. The frequency of NAA10-associated LMS is unknown.

6. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. An Irish family with microphthalmia/anophthalmia, ankyloblepharon and intellectual disability (MCOPS4) was previously mapped to Xq27-q28 [Graham et al 1991]. No causative gene has been identified (one individual from this family was screened for an NAA10 mutation and none was found [Esmailpour et al 2014].

Clinical Description

Natural History

The phenotype of Lenz microphthalmia syndrome, microphthalmia with developmental delay and skeletal and urogenital anomalies associated with NAA10 (MCOPS1 locus) cannot easily be distinguished from the LMS phenotype caused by the missense mutation p.Pro85Leu in BCOR (MCOPS2 locus). It is difficult to make phenotypic comparisons between MCOPS1 and MCOPS2 as only one family has been identified with an NAA10 mutation. Affected males with NAA10 splice mutation c.471+2T>A exhibited a greater degree of cognitive impairment, gastrointestinal symptoms, two-three toe cutaneous syndactyly with short terminal phalanges in the hand, and development of scoliosis and neuropathic muscle degeneration over time. These findings have not been reported in males with LMS caused by the BCOR variant p.Pro85Leu.

Lenz microphthalmia syndrome has a wide spectrum of ocular and extraocular abnormalities.

Eyes. The eyes may be asymmetrically affected. One globe can be of normal size while the other is microphthalmic. Severity can range from mild microphthalmia with retained vision to severe microphthalmia or clinical anophthalmia with blindness. Microphthalmia is often accompanied by microcornea and reduction in the size of the anterior segment of the eye, which predispose to the development of glaucoma.

Since mild microphthalmia may not be obvious on clinical examination, individuals with LMS with retained vision may not be identified until the first ophthalmologic examination when high hyperopia (+7 to +11 diopters) secondary to a foreshortened posterior segment of the globe is diagnosed.

Cataracts may be present.

Nystagmus may be present secondary to impaired vision.

Absence or diminished size of the globe may cause secondary underdevelopment of the bony orbits, shortened palpebral fissures, and fusion of the eyelid margins (ankyloblepharon).

Craniofacial. The occurrence of congenital microcephaly is variable. Affected individuals may be normocephalic or dolichocephalic.

Ears may be low set, anteverted, posteriorly rotated, simple, cup shaped, or abnormally modeled. Preauricular tags may be present.

Hearing loss has been observed.

Cleft lip/palate or high arched palate is present in approximately 12/30 of individuals [Ng et al 2002].

Dental development may be delayed. Nonspecific dental findings include irregularly shaped, missing, or widely spaced teeth.

Genitourinary. Urogenital anomalies are the most frequent associated findings, reported in approximately 23/30 of individuals [Ng et al 2002]. These include hypospadias, cryptorchidism, renal hypoplasia/aplasia, and hydroureter.

Limbs. Hand findings include duplicated and/or proximally placed thumbs, cutaneous syndactyly, clinodactyly, and camptodactyly.

Skeletal. Long cylindric thorax with sloping, narrow shoulders, underdeveloped clavicles, or thinning of the lateral third of the clavicles on x-ray as well as kyphoscoliosis and exaggerated lumbar lordosis have been seen in some families.

Cognitive/neurologic. Cognitive impairment varies within and among families. Approximately 22/35 of affected males have mild-to-severe intellectual disability or developmental delay [Ng et al 2002].

Motor development may be delayed.

Seizures, behavioral disturbance, and self-mutilation may manifest in males with severe intellectual disability. Sleep-wake cycles can be disturbed because of lack of normal diurnal variation.

Cranial MRI often reveals absent or hypoplastic optic nerves and optic chiasm. In addition, hypoplasia of the corpus callosum and cingulate gyrus has been noted. The latter is often clinically silent.

Heterozygotes. Features of LMS and OFCD have not been reported in female carriers of the BCOR variant p.Pro85Leu. In one family, two-three toe cutaneous syndactyly and short terminal phalanges in the hand were reported in female carriers of NAA10 variant c.471+2T>A [Esmailpour et al 2014].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Males reported with LMS and a BCOR pathogenic variant had the p.Pro85Leu pathogenic variant; however, one reported male exhibited radioulnar synostosis, which occurs in 7/35 of those with oculofaciocardiodental (OFCD) syndrome (see Genetically Related Disorders). Thus, the presence of radioulnar synostosis in a male with LMS may indicate the presence of a BCOR pathogenic variant [Hilton et al 2009].

Penetrance

An insufficient number of cases of Lenz microphthalmia exist to comment on penetrance.

Nomenclature

Lenz microphthalmia syndrome (LMS) has been referred to as Lenz dysplasia, Lenz dysmorphogenetic syndrome, and microphthalmia with associated anomalies. The two loci were formerly designated MAA and MAA2 (or ANOP2).

The locus designations MAA (now associated with syndromic microphthalmia 1 [MCOPS1, NAA10]), and MAA2 (now associated with syndromic microphthalmia 2 [MCOPS2, BCOR]) were used to highlight the genetic heterogeneity of LMS and the associated extraocular developmental anomalies and intellectual disability that co-occur with the microphthalmia in affected males.

MCOPS2 has since been redesignated oculofaciocardiodental syndrome (OFCD) due to the higher prevalence of BCOR loss-of-function mutations with OFCD. However, the BCOR p.Pro85Leu missense mutation remains a known cause of LMS.

Although the consensus inheritance pattern is X-linked recessive, the term Lenz microphthalmia is used by clinicians for simplex cases (i.e., single occurrence in a family) with a Lenz-like phenotype.

Prevalence

Prevalence in ethnic groups is unknown. Most reported cases are of European descent. BCOR p.Pro85Leu appears to be pan ethnic and has been reported in an African American family [Ng et al 2002], a European family [Hilton et al 2009], and two Japanese families [Suzumori et al 2013]. NAA10 c.471+2T>A has been found in one family of mixed European descent [Esmailpour et al 2014].

Differential Diagnosis

See Anophthalmia/Microphthalmia Overview.

A Hispanic family with isolated X-linked colobomatous microphthalmia has been reported [Lehman et al 2001] and an American family of European descent with syndromic X-linked colobomatous microphthalmia has been identified with a frameshift mutation in HMGB3 [Scott et al 2014].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Lenz microphthalmia syndrome (LMS), the following evaluations are recommended:

  • Physical examination for the presence of anomalies associated with the disorder
  • Cranial MRI to estimate the size of the globes for prognosis regarding potential visual function and to detect concurrent CNS malformations such as hypoplastic corpus callosum and cingulate gyrus
  • Visual evoked response testing and ophthalmologic examination to help determine visual acuity and/or the potential for vision
  • Consideration of echocardiogram if physical exam detects findings suggestive of a congenital cardiac malformation. (A single case report from Japan described an infant with a molecularly confirmed LMS (BCOR p.Pro85Leu) dying of an unspecified cardiac defect at age six months [Suzumori et al 2013].)
  • Renal ultrasound examination to evaluate for renal aplasia, hypoplasia, and hydroureter
  • Consideration of hearing evaluation during infancy if:
    • Head and neck examination reveals malformations of the auricle or ear canal, presence of skin tags or dimples around the ear, presence of cleft lip or palate, asymmetric facies, and microcephaly
    • The parents have concerns that the child cannot hear (e.g., infant does not startle to loud noises, awaken to sound). The type of examination should be adjusted for the individual's cognitive level to allow for cooperation and maximize the chance of an informative test (see Deafness and Hereditary Hearing Loss Overview).
  • Consideration of sleep evaluation if parents report excessive daytime somnolence, altered sleep-wake cycles, difficulty awakening the child or getting the child to fall asleep, apnea, loud snoring, and/or difficulty breathing while asleep
  • Medical genetics consultation

Treatment of Manifestations

Individuals with anophthalmos or extreme microphthalmos benefit from regular evaluations by an ocularist for placement of serial enlarging orbital expanders to prevent deformation of facial structures and to encourage normal development of eye lashes and lid margins.

Early intervention with physical therapy and occupational therapy helps to address disturbances of the sleep-wake cycle caused by lack of light perception and problems of delayed gross motor development often observed in children with visual impairment.

Early intervention with special education maximizes cognitive development.

Referral to services for the visually impaired is recommended.

Treatment for hearing loss and sleep disorders is dependent on the specific defect and similar to the general population.

Referral to a sleep disorder specialist may be necessary depending on the individual's history and presentation to determine the appropriate tests.

Dental examinations and cleaning should be instituted to monitor dental hygiene, especially when the affected individual has cognitive developmental delay. Missing and irregularly shaped teeth and wide spacing of teeth are common. Treatment is the same as for the general population in restoring masticatory function.

Prevention of Secondary Complications

No special preventative care is recommended. Follow-up care is personalized based on the physical impairments found in the individual.

Surveillance

The following are appropriate:

  • Annual ophthalmologic examination for those with residual vision given the predisposition to glaucoma and high hyperopia from foreshortening of the globe
  • Monitoring of renal function (BUN, creatinine, and urine analysis) in those with known renal/ureteral anomalies
  • Developmental assessments performed with each well-child visit as recommended by the American Academy of Pediatrics. More frequent and specialized assessments are tailored to each child if development is not on track.
  • Lifelong case management to help affected individuals gain access to social services and assistive devices for the blind

Agents/Circumstances to Avoid

In those with residual vision, dilating drops and medications that may dilate the pupils (i.e., antihistamines, decongestants, tricyclic antidepressants) should be used in consultation with an ophthalmologist because of the narrow anterior chamber and risk for angle closure glaucoma.

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 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Lenz microphthalmia syndrome is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

  • The father of an affected male will neither have the disease nor be a carrier of a BCOR or NAA10 pathogenic variant.
  • In a family with more than one affected male, the mother of an affected male is an obligate carrier.
  • If only one male in the family is affected, the mother may be a carrier or the affected male may have a de novo mutation, in which case the mother is not a carrier. The frequency of de novo mutations is not known. To date, all published cases have been inherited.
  • To date there are no reports of germline mosaicism in a mother.

Sibs of a proband. The risk to sibs depends on the carrier status of the mother:

  • If the mother of the proband has a BCOR or NAA10 pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be carriers.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. The majority of males with Lenz microphthalmia syndrome do not have children, possibly as a result of infertility or decreased reproductive fitness secondary to cognitive impairment. Males who are capable of reproducing pass the pathogenic variant to all of their daughters and none of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing for at-risk females requires prior identification of the BCOR or NAA10 pathogenic variant in the family.

Note: Carriers are heterozygous for this X-linked disorder and are generally asymptomatic (see Natural History, Heterozygotes).

Related Genetic Counseling Issues

Family planning

  • The optimal time for discussion of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the BCOR or NAA10 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Ultrasound examination. Prenatal ultrasound examination at 18 weeks' gestation can be offered for pregnancies at increased risk to evaluate fetal renal development. No data exist regarding the effectiveness of screening for other malformations in fetuses at risk for LMS, although prenatal ultrasound at 15 weeks’ gestation found evidence of unopened palpebral fissures suggestive of underdeveloped eyes [Suzumori et al 2013].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the BCOR or NAA10 pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • International Children's Anophthalmia and Microphthalmia Network (ICAN)
    c/o Center for Developmental Medicine and Genetics
    5501 Old York Road
    Genetics, Levy 2 West
    Philadelphia PA 19141
    Phone: 800-580-4226 (toll-free)
    Email: ican@anophthalmia.org
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • National Federation of the Blind (NFB)
    200 East Wells Street
    (at Jerigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
    Email: pmaurer@nfb.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Lenz Microphthalmia Syndrome: Genes and Databases

Locus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
MCOPS1NAA10Xq28N-alpha-acetyltransferase 10 NAA10
MCOPS2BCORXp11​.4BCL-6 corepressorBCOR @ LOVDBCOR

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Lenz Microphthalmia Syndrome (View All in OMIM)

300013N-ALPHA-ACETYLTRANSFERASE 10, NatA CATALYTIC SUBUNIT; NAA10
300485BCL6 COREPRESSOR; BCOR
309800MICROPHTHALMIA, SYNDROMIC 1; MCOPS1

BCOR

Gene structure. BCOR extends over approximately 55 kb and includes 15 exons. The reference cDNA for BCOR isoform 1 is 6182 bp (NM_017745.5). The open reading frame is 5163 bp. BCOR isoform 2 is 3676 bp. BCOR long isoform, alternatively spliced is 5810 bp (AY316592.1). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Four families have been reported with males affected with Lenz microphthalmia syndrome (LMS) due to (MCOPS2) c.254C>T (p.Pro85Leu) [Ng et al 2004, Hilton et al 2009, Suzumori et al 2013].

Table 2. BCOR Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.254C>Tp.Pro85LeuNM_017745​.5
NP_060215​.4

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. BCOR isoform 1 encodes a protein of 1721amino acids. BCOR isoform 2 encodes a protein of 1004 amino acids. BCOR long isoform, alternatively spliced encodes a protein of 1755 amino acids.

Abnormal gene product. The p.Pro85Leu pathogenic variant is expressed and results in perturbation of ocular and extraocular organ development. Truncated and abnormally spiced variants of BCOR have not been detected in individuals with OFCD syndrome and are hypothesized to be eliminated by nonsense-mediated mRNA decay.

NAA10

Gene structure. NAA10 isoform 1 encodes a protein consisting of 235 amino acids. NAA10 isoform 2 encodes a protein consisting of 220 amino acids and isoform 3 encodes a protein of 229 amino acids. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The c.471+2T>A pathogenic variant affects the NAA10 canonical splice donor site of intron 7. Primers amplifying the NAA10 cDNA of exons 5 through 8 showed the presence of an abnormal exon7-intron7-exon8 fusion product (mutant splice variant 1) and no wild-type cDNA product was present in affected males [Esmailpour et al 2014].

Table 3. NAA10 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.471+2T>AUnknownNM_003491​.3
NP_003482​.1

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. NAA10 codes for the catalytic subunit of the N-terminal acetyl transferase (hNatA) [Starheim et al 2009, Rope et al 2011]. N-terminal acetylation (NAT) of proteins is one of the most common protein modifications [Arnesen 2009]. It is estimated that hNatA has over 8000 human protein substrates [Starheim et al 2009]; hNatA complex is highly conserved from yeast. Knockdown experiments of hNatA affected substrates involved in protein-protein interactions, transcriptional regulation, ribosome assembly, RNA maturation, and protein folding and modification [Starheim et al 2009].

Abnormal gene product. A lower molecular weight protein compared to wild-type control was present in one affected male suggesting the presence of a truncated NAA10 protein; protein sequencing was not performed. Fibroblasts derived from affected males showed deficient growth compared to normal control. Western blot analysis of fibroblast derived protein from an affected male showed no detectable wild-type NAA10 protein [Esmailpour et al 2014]. Results from gene expression profile from three affected males suggested perturbation of the retinoic signaling pathway [Esmailpour et al 2014].

References

Literature Cited

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  4. Forrester S, Kovach MJ, Reynolds NM, Urban R, Kimonis V. Manifestations in four males with and an obligate carrier of the Lenz microphthalmia syndrome. Am J Med Genet. 2001;98:92–100. [PubMed: 11426460]
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  8. Lehman DM, Sponsel WE, Stratton RF, Mensah J, Macdonald JC, Johnson-Pais TL, Coon H, Reveles XT, Cody JD, Leach RJ. Genetic mapping of a novel X-linked recessive colobomatous microphthalmia. Am J Med Genet. 2001;101:114–9. [PubMed: 11391653]
  9. Ng D, Hadley DW, Tifft CJ, Biesecker LG. Genetic heterogeneity of syndromic X-linked recessive microphthalmia-anophthalmia: is Lenz microphthalmia a single disorder? Am J Med Genet. 2002;110:308–14. [PubMed: 12116202]
  10. Ng D, Thakker N, Corcoran CM, Donnai D, Perveen R, Schneider A, Hadley DW, Tifft C, Zhang L, Wilkie AO, van der Smagt JJ, Gorlin RJ, Burgess SM, Bardwell VJ, Black GC, Biesecker LG. Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR. Nat Genet. 2004;36:411–6. [PubMed: 15004558]
  11. Oberoi S, Winder AE, Johnston J, Vargervik K, Slavotinek AM. Case reports of oculofaciocardiodental syndrome with unusual dental findings. Am J Med Genet A. 2005;136:275–7. [PubMed: 15957158]
  12. Rope AF, Wang K, Evjenth R, Xing J, Johnston JJ, Swensen JJ, Johnson WE, Moore B, Huff CD, Bird LM, Carey JC, Opitz JM, Stevens CA, Jiang T, Schank C, Fain HD, Robison R, Dalley B, Chin S, South ST, Pysher TJ, Jorde LB, Hakonarson H, Lillehaug JR, Biesecker LG, Yandell M, Arnesen T, Lyon GJ. Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency. Am J Hum Genet. 2011;89(1):28–43. [PMC free article: PMC3135802] [PubMed: 21700266]
  13. Scott AF, Mohr DW, Kasch LM, Barton JA, Pittiglio R, Ingersoll R, Craig B, Marosy BA, Doheny KF, Bromley WC, Roderick TH, Chassaing N, Calvas P, Prabhu SS, Jabs EW. Identification of an HMGB3 Frameshift Mutation in a Family With an X-linked Colobomatous Microphthalmia Syndrome Using Whole-Genome and X-Exome Sequencing. JAMA Ophthalmol. 2014 Jul 3. Epub ahead of print. [PubMed: 24993872]
  14. Starheim KK, Gromyko D, Velde R, Varhaug JE, Arnesen T. Composition and biological significance of the human Nalpha-terminal acetyltransferases. BMC Proc. 2009;3 Suppl 6:S3. [PMC free article: PMC2722096] [PubMed: 19660096]
  15. Suzumori N, Kaname T, Muramatsu Y, Yanagi K, Kumagai K, Mizuno S, Naritomi K, Saitoh S, Sugiura-Ogasawara M. Prenatal diagnosis of X-linked recessive Lenz microphthalmia. J Obstet Gynaecol Res. 2013;39:1545–7. [PubMed: 23815237]

Suggested Reading

  1. Martínez-Garay I, Tomás M, Oltra S, Ramser J, Moltó MD, Prieto F, Meindl A, Kutsche K, Martínez F. A two base pair deletion in the PQBP1 gene is associated with microphthalmia, microcephaly, and mental retardation. Eur J Hum Genet. 2007;15:29–34. [PubMed: 17033686]

Chapter Notes

Revision History

  • 2 October 2014 (me) Comprehensive update posted live
  • 29 April 2010 (me) Comprehensive update posted live
  • 27 July 2007 (cd) Revision: clinical testing for BCOR mutations no longer available
  • 6 September 2006 (cd) Revision: FISH, mutation scanning, linkage analysis, and X-chromosome inactivation studies no longer clinically available for BCOR
  • 23 June 2006 (ca) Comprehensive update posted to live Web site
  • 12 April 2005 (dn) Revision: BCOR testing clinically available
  • 13 May 2004 (me) Comprehensive update posted to live Web site
  • 5 February 2004 (dn) Revision: Molecular Genetics
  • 4 June 2002 (me) Review posted to live Web site
  • 8 February 2002 (dn) Original submission

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