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Polymicrogyria Overview

, MBBS, FRACP, , MD, , MD, PhD, , MD, and , MBBS, BMedSci, PhD, FRACP.

Author Information

Initial Posting: ; Last Update: August 16, 2018.

Estimated reading time: 17 minutes

Summary

The following are the goals of this overview.

Goal 1.

Describe the neuroimaging characteristics of polymicrogyria (PMG).

Goal 2.

Review the genetic causes of PMG.

Goal 3.

Provide an evaluation strategy to identify the genetic cause of PMG in a proband (when possible).

Goal 4.

Inform genetic counseling of family members of a proband with PMG.

1. Definition and Clinical Characteristics of Polymicrogyria

Polymicrogyria (PMG) is a malformation of the developing brain characterized by abnormal cortical lamination and an unusual folding pattern of the cerebral cortex such that all or part of the brain surface is taken up by an excessive number of small gyri (folds). PMG, one of the most common brain malformations, accounts for approximately 20% of all malformations of cortical development [Leventer et al 1999].

MRI. The diagnosis of PMG is typically made by MRI since computed tomography (CT) and other imaging methods do not have high enough resolution or adequate contrast to identify the small folds that define PMG. It is important that optimal imaging techniques (including thin sections) and age-specific protocols be used to provide the best contrast between gray and white matter with good spatial resolution and adequate signal-to-noise ratio [Barkovich 2010].

With high-quality MRI, microgyri and microsulci may be appreciated and stippling of the gray-white junction (a specific feature of PMG not seen in other malformations of cortical development) may be observed [Leventer et al 2010] (see Table 1). Of note, the Sylvian fissures (best seen on sagittal imaging) should be scrutinized in particular, as PMG often affects these areas preferentially.

While PMG is usually an isolated finding (i.e., occurring in the absence of other brain malformations), it can be seen in association with other brain malformations including gray matter heterotopia and ventriculomegaly, as well as abnormalities of the white matter, corpus callosum, brain stem, and cerebellum.

MRI – when interpreted by an expert – can reliably differentiate PMG from other malformations of cortical development (see Differential Diagnosis).

Prenatal ultrasound examination. In 5% of cases, PMG is detected on prenatal ultrasound examination by the presence of abnormalities – usually microcephaly and/or associated brain malformations. Note: PMG is difficult to detect by ultrasound examination until late in gestation [Leventer et al 2010].

Table 1.

Patterns of PMG: MRI and Clinical Findings

PMG PatternAffected RegionsMRI Findings
Bilateral
perisylvian
PMG (BPP)
Image poly-Image001.jpg Bilateral PMG maximal in perisylvian regions (arrows), which may be symmetric or asymmetric & may extend beyond perisylvian regions; sylvian fissures often extended posteriorly & superiorly
Unilateral
perisylvian
PMG (UPP)
Image poly-Image002.jpg Unilateral PMG maximal in perisylvian cortex (arrow), but may extend beyond perisylvian region; sylvian fissure often extended posteriorly & superiorly
Bilateral
generalized
PMG (BGP)
Image poly-Image003.jpg Symmetric generalized PMG w/no obvious gradient or region of maximal severity; may have abnormal high signal in white matter
Bilateral frontal
PMG (BFP)
Image poly-Image004.jpg Symmetric PMG w/anterior > posterior gradient extending from frontal poles (arrows) posteriorly to precentral gyrus & inferiorly to frontal operculum
Bilateral
frontoparietal
PMG (BFPP)
Image poly-Image005.jpg Symmetric generalized PMG with decreasing anterior-posterior gradient, most prominent in frontoparietal cortex (arrows)
Bilateral
parasagittal
parieto-occipital
PMG (BPPP)
Image poly-Image006.jpg Bilateral PMG in parasagittal & mesial aspects of parieto-occipital cortex (arrows)
PMG associated
w/periventricular
nodular
heterotopia
(PNH-PMG)
Image poly-Image007.jpg PMG of variable patterns (mainly perisylvian or parieto-occipital) (large arrows) associated w/nodules of periventricular gray matter heterotopia (arrowheads)

All MRI images are T2-weighted axial.

Bilateral perisylvian PMG (BPP), the most common pattern of PMG, is associated with oromotor dysfunction and a seizure disorder. Other findings typically include difficulties with tongue movement, expressive speech, and sucking and swallowing, as well as excessive drooling and facial diplegia as seen in the Worster-Drought syndrome. Mild-moderate intellectual disability is seen in up to 75%. Motor dysfunction may include limb spasticity, which – if present – is rarely severe [Kuzniecky et al 1993].

For information on neuropathology of PMG click here (pdf).

Differential Diagnosis

Other malformations of cortical development that need to be distinguished from PMG:

  • Pachygyria/lissencephaly, a distinct brain malformation in which reduced or absent cortical folding is combined with a thick cortex. Pachygyria and PMG may look similar on low-resolution neuroimaging (e.g., CT) because in both conditions the cortical thickness can appear to be increased and the gyri can appear to be broad and smooth. The cortex in PMG is overfolded but not thickened. The microgyri and microsulci of PMG and stippling of the gray-white junction that can be appreciated with high-quality MRI can distinguish PMG from pachygyria [Leventer et al 2010].
  • Cobblestone lissencephaly, a brain surface that has a bumpy contour resulting from migration of neurons and glial cells through the basement membrane into the leptomeninges. Sometimes regions populated by these misplaced cells are incorrectly initially diagnosed as PMG based on the MRI appearance and are only distinguished from PMG by the presence of other brain abnormalities (e.g., white matter and cerebellar abnormalities) in combination with ocular anomalies and congenital muscular dystrophy. The cobblestone lissencephalies comprise brain malformations associated with congenital muscular dystrophy, including Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy.
  • Schizencephaly, a specific pattern of PMG that describes a full-thickness cleft in the brain lined by PMG. While either CT or MRI is usually sufficient to diagnose schizencephaly, MRI is preferred when determining if the schizencephaly is open- or closed-lipped.

2. Genetic Causes of Polymicrogyria

Genetic causes of polymicrogyria (PMG) include both contiguous-gene and single-gene disorders.

Contiguous-Gene Disorders

PMG has been implicated in a number of chromosome copy number variants (CNVs) (summarized in Robin et al [2006], Dobyns et al [2008]).

The most common copy number variants associated with PMG:

  • 22q11.2 deletion, characterized by cardiac defects, parathyroid hypoplasia, facial dysmorphism, and thymus hypoplasia, ± microcephaly and bilateral perisylvian PMG
  • 1p36 deletion (OMIM 607872), characterized by developmental delay / intellectual disability and dysmorphic facial features, ± microcephaly and bilateral perisylvian PMG

Other copy number variants with which PMG may be associated are deletion of 4q21, 6q26, 13q3, 18p11, and 21q2 and duplication of 2p13 [Guerrini & Dobyns 2014].

Single-Gene Disorders

To date more than 40 genes have been associated with PMG. This GeneReview covers the following pathways and groups of related disorders implicated in PMG:

  • The mTORopathies (the PI3K-AKT-MTOR pathway)
  • The tubulinopathies
  • Cobblestone dysplasia – alpha dystroglycanopathies
  • Cobblestone dysplasia – other (including laminopathies and congenital disorders of glycosylation)
  • Other pathways/pathologies

Table 2 presents the genes associated with the above categories (in alphabetic order within each category). Several conditions with PMG are described in more detail following Table 2.

Additional disorders not included in Table 2 are Aicardi syndrome (in which PMG is almost uniformly seen) [Hetts et al 2006], and the monogenic syndromes Mowat-Wilson syndrome, Yunis Varon syndrome [Baulac et al 2014], Adams-Oliver syndrome [Amor et al 2000], and Sturge-Weber syndrome (in all of which PMG is seen at low frequency).

Table 2.

PMG-Associated Genes Grouped by Pathway/Pathology

Pathway/
Pathology
Gene 1Head Size 2Brain FindingsDisorder NameMOIReference 3
MACMICN/MS
mTORopathies AKT3 xBilateral perisylvian PMGMPPH syndromeAD MPPH Syndrome
CCND2 x
MTOR xSmith-Kingsmore syndromeADOMIM 616638
PI4KA xPerisylvian PMGAROMIM 616531
PIK3CA xBilateral perisylvian PMGMCAP syndromeSee footnote 5. PIK3CA-Related Segmental Overgrowth
PIK3R2 xMPPH syndromeAD MPPH Syndrome
PTEN xDiffuse, focal, or multifocal PMGADElia et al [2012], Saletti et al [2017]
Tubulinopathies DYNC1H1 xxFrontal or diffuse PMGADOMIM 600112
KIF5C xPerisylvian PMGADOMIM 615282
TUBA1A xxDiffuse, focal, or multifocal PMG; bilateral, asymmetric, perisylvian PMGLissencephaly 3AD Tubulinopathies Overview
TUBB xPMGAD
TUBB2A xBilateral, asymmetric, anterior predominant PMGAD
TUBB2B xx
TUBB3 xxFrontoparietal PMGAD
Cobblestone dysplasia – alpha dystroglycan-opathies FKTN xDiffuse (cerebral & cerebellar) PMGAR Fukuyama Congenital Muscular Dystrophy
POMGNT1 xPMGAROMIM 606822
POMT2 xPMGAROMIM 607439
Cobblestone dysplasia – other (incl laminopathies & congenital disorders of glycosylation) ADGRG1 (GPR56)xBilateral frontoparietal PMGAROMIM 604110
COL3A1 xxDiffuse cobblestone cortex; PMG A > PAR Horn et al [2017]
ATP6V0A2 xxFrontoparietal PMGAutosomal recessive cutis laxa type 2AAR ATP6V0A2-Related Cutis Laxa
LAMA2 xOccipital PMG; white-matter signal abnormalitiesMuscular dystrophy, congenital merosin-deficient, 1AAROMIM 607855
LAMB1 xxPorencephaly; cobblestone lissencephaly P > ALissencephaly 5AROMIM 615191
LAMC3 xOccipital PMGAROMIM 614115
SNAP29 xPerisylvian or diffuse PMGAROMIM 609528
SRD5A3 xFrontal PMGSRD5A3-CDG (CDG-Iq)AR Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview
Other BICD2 xPerisylvian PMGAD Ravenscroft et al [2016]
COL18A1 xFrontal PMGKnobloch syndrome 1AR Keren et al [2007]
DDX3X xxFrontoparietal or diffuse PMGDDX3X-related neurodevelopmental disorderXL DDX3X-Related Neurodevelopmental Disorder
EML1 xRibbon-like heterotopia w/overlying PMG; ACCAROMIM 600348
EOMES (TBR2)xBilateral perisylvian or diffuse PMGAROMIM 604615
EZH2 xBilateral perisylvian PMGWeaver syndromeAD EZH2-Related Overgrowth
FIG4 xxBilateral or temporo-occipital PMGAROMIM 612691
GPSM2 xParasagittal PMG; ACCChudley-McCollough syndromeAROMIM 604213
GRIN1 xExtensive bilateral PMGAD GRIN1-Related Neurodevelopmental Disorder
GRIN2B xxDiffuse PMGAD GRIN2B-Related Neurodevelopmental Disorder
KIFBP (KIAA1279)xDiffuse PMGGoldberg-Shprintzen syndromeAROMIM 609460
MAP1B Perisylvian PMG; PNHAD Heinzen et al [2018]
NDE1 xDiffuse PMGAROMIM 609449
NEDD4L xBilateral perisylvian PMG; PNHAD Kato et al [2017]
OCLN xBand-like calcifications w/diffuse PMGPseudo-TORCH syndrome 1AROMIM 251290
OFD1 xFrontal and parietal PMGJoubert syndrome (XLR); orofaciodigital syndrome 1 (XLD)XL Joubert Syndrome
PAX6 xVariable temporal PMGAROMIM 607108
RAB18 xxDiffuse or frontal PMGRAB18 deficiency 4AR RAB18 Deficiency
RAB3GAP1 xx
RAB3GAP2 xx
RTTN xVariable diffuse, asymmetric PMGAROMIM 614833
TBC1D20 xDiffuse or bilateral frontal PMGRAB18 deficiency 4AR RAB18 Deficiency
TCTN1 xFrontal PMGJoubert syndromeAR Joubert Syndrome
TMEM216 xVariable PMGMeckel-Gruber syndrome, Joubert syndromeAR
WDR62 x± diffuse or asymmetric PMGAROMIM 604317

Note: The table does not list genes that can be associated with PMG and metabolic disorders (Table 3), disorders of peroxisomal biogenesis (see Zellweger Spectrum Disorder), or mitochondrial disorders (see Mitochondrial Disorders Overview).

A = anterior; ACC = absence of the corpus callosum; AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; MCAP = megalencephaly-capillary malformation-PMG; MOI = mode of inheritance; MPPH = megalencephaly-polymicrogyria-polydactyly-hydrocephalus; P = posterior; PNH = periventricular nodular heterotopia; XL = X-linked; XLD = X-linked dominant; XLR = X-linked recessive

1.

Genes are in alphabetic order.

2.

Head size:
N/MS = normal / mildly small (i.e., head circumference >3 SD and <97%)
MIC = severe microcephaly (i.e., birth head circumference <3 SD or earliest HC <4 SD)
MAC = macrocephaly (i.e., head circumference >97%)

3.

GeneReview, citation, or OMIM entry

4.

RAB18 deficiency is a spectrum that includes Warburg micro syndrome (at the severe end) and Martsolf syndrome (at the mild end). Additional findings are eye involvement (bilateral congenital cataracts, microphthalmia, and microcornea); severe-to-profound intellectual disability; and hypogonadism.

5.

Most affected individuals with MCAP reported to date (21/24) had somatic mosaicism for pathogenic variants in PIK3CA, suggesting that mutation occurred post fertilization in one cell of the multicellular embryo. Two of 24 affected individuals had a de novo germline pathogenic variant in PIK3CA.

Tubulinopathies (see Tubulinopathies Overview) are caused by a heterozygous pathogenic variant in TUBA1A (see Note), TUBB, TUBB2A, TUBB2B, or TUBB3 – genes encoding different isotypes of α-tubulin. Brain malformations include asymmetric perisylvian PMG with callosal defects, cerebellar vermis dysplasia, pontine hypoplasia, and dysmorphic basal ganglia. Because dysmorphic basal ganglia [Amrom et al 2014] and atypical microgyration (which may not be as evident as in typical PMG) are common in tubulin-associated PMG, it has been proposed that these complex cortical malformations be called "tubulin-associated dysgyria."

Note: While heterozygous pathogenic variants in TUBA1A can be associated with PMG, they are more frequently associated with pachygyria [Jansen et al 2011].

ADGRG1 (formerly GPR56). The spectrum of brain malformations includes the relatively rare phenotype of bilateral frontoparietal-predominant PMG [Piao et al 2005], a cobblestone-like lissencephaly (with no eye or muscle involvement), cerebellar dysplasia, and diffuse myelination abnormalities [Dobyns et al 1996, Bahi-Buisson et al 2010]. Although biallelic ADGRG1 pathogenic variants were initially reported as a cause of bilateral frontoparietal PMG (BFPP), subsequent reports and further delineation of the phenotype showed that the cortical malformation was most often cobblestone in nature or complex cortical dysgyria resembling PMG, rather than typical PMG [Bahi-Buisson et al 2010].

Metabolic disorders most commonly reported with PMG are summarized in Table 3.

Table 3.

Selected Metabolic Disorders Commonly Associated with PMG

DisorderReference (GeneReview or OMIM)
Classic nonketotic hyperglycinemia Classic Nonketotic Hyperglycinemia
Fumaric aciduria 1OMIM 136850
Glutaric acidemia type II Multiple Acyl-CoA Dehydrogenase Deficiency
HistidinemiaOMIM 235800
Maple syrup urine disease Maple Syrup Urine Disease
Mitochondrial disorders Mitochondrial Disorders Overview
Pyruvate dehydrogenase deficiencyOMIM PS312170
Zellweger spectrum disorder 1 Zellweger Spectrum Disorder
1.

Zellweger syndrome and fumaric aciduria are the most common metabolic causes of PMG of those addressed in Table 3. Zellweger syndrome and fumaric aciduria are typically identified by additional clinical features.

3. Evaluation Strategy to Identify the Genetic Cause of PMG in a Proband

The approach outlined in this section can be used to determine if a specific genetic cause or mode of inheritance can be identified to aid in discussions of prognosis and genetic counseling.

Confirming the Clinical Diagnosis

Confirming PMG as the underlying cortical malformation and ruling out other brain malformations that may be confused with PMG (e.g., pachgyria and other forms of cortical dysplasia) requires consultation with an expert in interpretation of the MRI findings of PMG. Note that while the gold standard for the diagnosis of PMG is postmortem histopathologic examination, the clinical diagnosis relies on neuroimaging.

History

Pregnancy. A detailed pregnancy history with attention to infections, trauma, multiple gestations, and other documented problems that could provide insight into possible acquired causes of PMG. PMG is commonly associated with congenital cytomegalovirus [Kwak et al 2018].

Family. Parental consanguinity may suggest an autosomal recessive disorder (Table 2).

If no genetic cause has been identified and if familial PMG is suspected, it may be reasonable to perform a brain MRI (if not previously performed) on close relatives (i.e., parents or sibs) with the following:

  • Neurologic problems including seizures, cognitive delay, motor impairment, pseudobulbar signs, and/or focal weakness
  • What appear to be minor findings, such as a lisp or an isolated learning disability

Medical. Other specific tests targeting individual neurometabolic disorders can be obtained if clinically suggested (see Table 3).

Physical Examination

Head size is a useful first step in clinical assessment to aid in focusing genetic testing.

Macrocephaly is the group in which a genetic cause of PMG is most likely to be identified. The most common disorders with macrocephaly are the PI3K-AKT-MTOR-related disorders. Diagnostic possibilities:

  • In the absence of systemic findings: MPPH syndrome
    Note that a subset of individuals have hydrocephalus (requiring shunting) and/or polydactyly of fingers/toes.
  • In the presence of other systemic features such as somatic overgrowth or pigmentary skin changes:
    • MCAP (vascular-lymphatic abnormalities)
    • MTOR-related disorders (linear pigmentary skin changes)
    • PTEN-related disorders (features of PTEN-hamartoma tumor syndrome)

Microcephaly, a highly genetically heterogeneous group that includes numerous multisystem disorders, requires thorough physical assessment and detailed review of the brain MRI findings. Diagnostic possibilities in the presence of:

  • Fetal brain disruption pattern on imaging:
    • NDE1-related lissencephaly
    • WDR62-related microcephaly
  • Complex additional brain malformations:

Normocephaly (or borderline microcephaly). The most commonly identified genetic factors are copy number variants resulting in disorders such as 22q11.2 deletion and 1p36 deletion (OMIM 607872), which involve multiple systems and have numerous additional features including (but not limited to) intellectual disability, dysmorphic facial features, and congenital heart defects.

A general physical examination should look for any associated craniofacial, musculoskeletal, and/or visceral findings that could indicate the mostly commonly considered syndromes (Table 2).

Molecular Genetic Testing

Testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and comprehensive genomic testing (exome sequencing, exome array, or chromosomal microarray analysis [CMA]). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not. Options include the following:

  • Serial single-gene testing can be considered if clinical findings and/or family history indicate that pathogenic variants in a particular gene are most likely (see Table 2). Sequence analysis of the most likely gene is performed first, followed by gene-targeted deletion/duplication analysis as indicated.
  • A PMG multigene panel that includes some or all of the genes listed in Table 2 is most likely to identify the genetic cause of PMG at the most reasonable cost 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. Of note, given the rarity of some of the genes associated with PMG, some panels may not include all of the genes listed in Table 2. (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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications that cannot be detected by sequence analysis may be considered in individuals with distinguishing phenotypic features suggestive of a contiguous gene deletion (see Genetic Causes of Polymicrogyria, Contiguous-Gene Disorders).
  • Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) may be considered. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

4. Genetic Counseling of Family Members of an Individual with PMG

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Genetic counseling. Hereditary polymicrogyria (PMG) may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Genetic counseling and risk assessment depend on determination of the specific genetic cause of PMG in an individual.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with PMG have an affected parent.
  • Many individuals diagnosed with PMG have the disorder as the result of a de novo pathogenic variant.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant (i.e., the proband appears to be the only affected family member) include molecular genetic testing.
  • The family history may appear to be negative because of failure to recognize the disorder in a family member or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing and/or clinical evaluation has been performed.
  • Note: Due to reduced penetrance, there may be asymptomatic family members or several generations of individuals with the pathogenic variant who remain symptom-free.

Sibs of a proband. The risk to sibs depends on the genetic status of the proband's parents: if one of the proband's parents has a PMG-related pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Note that phenotypic variability can be observed within families.

Offspring of a proband. Each child of an individual with autosomal dominant PMG has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the PMG-related pathogenic variant, his or her family members may be at risk.

Autosomal Recessive Inheritance

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one PMG-related pathogenic variant).
  • Heterozygotes are asymptomatic.

Sibs of a proband. At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier (heterozygote), and a 25% chance of being unaffected and not a carrier.

Offspring of a proband. All offspring are obligate heterozygotes (carriers) for a pathogenic variant in a PMG-related gene.

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

Carrier (Heterozygote) Detection

Carrier detection for at-risk relatives requires prior identification of the PMG-related pathogenic variants in the family.

X-Linked Inheritance

Risk to Family Members

Parents of a male proband

  • The father of an affected male will not have the disorder nor will he be hemizygous for the PMG-related pathogenic variant; therefore, he does not require further evaluation/testing.
  • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the PMG-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo pathogenic variant, in which case the mother is not a carrier.

Parents of a female proband. See Oral-Facial-Digital Syndrome Type I.

Sibs of a male proband. The risk to sibs depends on the genetic status of the proband's mother:

  • If the mother of the proband has the PMG-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes (carriers) and will not typically be affected.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the PMG-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism.

Sibs of a female proband. See Oral-Facial-Digital Syndrome Type I.

Offspring of a proband. Affected males will transmit 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 heterozygotes (carriers) for the pathogenic variant, and the aunts' offspring, depending on their gender, may be at risk of being heterozygotes (carriers) for the pathogenic variant or of being affected.

Heterozygote (Carrier) Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the PMG-related pathogenic variant has been identified in the proband.

Prenatal Testing and Preimplantation Genetic Testing

Once the PMG-related pathogenic variant(s) 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, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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.

  • PMG Awareness Organization, Inc.
    4533 MacArthur Boulevard
    Suite #5182
    Newport Beach CA 92660
    Phone: 949-329-5975
    Email: information@pmgawareness.org
  • National Library of Medicine Genetics Home Reference

References

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Chapter Notes

Author Notes

Dr Ghayda Mirzaa is a geneticist and researcher at Seattle Children's Hospital. The goal of her research is to study the underlying causes, natural history, and medical management of developmental brain disorders including brain malformations, autism, and epilepsy.

Acknowledgments

We acknowledge the assistance of Ms Stefanie Brock in the preparation of Table 2.

Author History

Kira Apse, ScM; Harvard Medical School (2004-2018)
Adria Bodell, MS, CGC; Harvard Medical School (2004-2018)
Bernard Chang, MD; Harvard Medical School (2004-2018)
William Dobyns, MD (2018-present)
Anna Jansen, MD, PhD (2018-present)
Richard J Leventer, MBBS, BMedSci, PhD, FRACP (2018-present)
Ghayda Mirzaa, MD (2018-present)
Chloe Stutterd, MBBS, FRACP (2018-present)
Christopher A Walsh, MD, PhD; Harvard Medical School (2004-2018)

Revision History

  • 16 August 2018 (bp) Comprehensive update posted live
  • 6 August 2007 (me) Comprehensive update posted live
  • 18 April 2005 (me) Overview posted live
  • 24 August 2004 (bc) Original submission
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