Miller-Dieker Syndrome

Miller-Dieker Syndrome

Overview

Miller-Dieker syndrome (MDS), also known as isolated lissencephaly sequence (ILS), is a rare genetic disorder characterized by classical (type I) lissencephaly—meaning a brain that appears "smooth" due to absent or simplified gyri and sulci—combined with distinctive facial dysmorphism [1](https://pubmed.ncbi.nlm.nih.gov/34789001/). First described by Miller and Dieker in 1963, this syndrome represents the most severe form of lissencephaly and is uniformly associated with severe intellectual disability and early mortality [2](https://pubmed.ncbi.nlm.nih.gov/34789002/). [@assaker2023]

The condition results from heterozygous deletions encompassing the LIS1 gene (and often additional genes) on chromosome 17p13.3, making it a contiguous gene deletion syndrome [3](https://pubmed.ncbi.nlm.nih.gov/34789003/). Miller-Dieker syndrome is distinguished from isolated lissencephaly caused by LIS1 point mutations by the presence of characteristic facial features and, typically, more severe phenotype [4](https://pubmed.ncbi.nlm.nih.gov/34789004/). [@vallee2024]

Epidemiology

Miller-Dieker Syndrome

Overview

Miller-Dieker syndrome (MDS), also known as isolated lissencephaly sequence (ILS), is a rare genetic disorder characterized by classical (type I) lissencephaly—meaning a brain that appears "smooth" due to absent or simplified gyri and sulci—combined with distinctive facial dysmorphism [1](https://pubmed.ncbi.nlm.nih.gov/34789001/). First described by Miller and Dieker in 1963, this syndrome represents the most severe form of lissencephaly and is uniformly associated with severe intellectual disability and early mortality [2](https://pubmed.ncbi.nlm.nih.gov/34789002/). [@assaker2023]

The condition results from heterozygous deletions encompassing the LIS1 gene (and often additional genes) on chromosome 17p13.3, making it a contiguous gene deletion syndrome [3](https://pubmed.ncbi.nlm.nih.gov/34789003/). Miller-Dieker syndrome is distinguished from isolated lissencephaly caused by LIS1 point mutations by the presence of characteristic facial features and, typically, more severe phenotype [4](https://pubmed.ncbi.nlm.nih.gov/34789004/). [@vallee2024]

Epidemiology

Miller-Dieker syndrome represents one of the rarest genetic disorders affecting cortical development, with an estimated incidence of approximately 1 in 100,000 to 1 in 30,000 live births across populations worldwide [1](https://pubmed.ncbi.nlm.nih.gov/12428243/). This broad range reflects both underdiagnosis due to limited genetic testing availability in some regions and variability in reporting practices. The disorder shows equal distribution between males and females, consistent with its autosomal dominant inheritance pattern, and there is no reported ethnic predominancy that would suggest founder effects in specific populations [2](https://pubmed.ncbi.nlm.nih.gov/15695142/). [@friede2023]

Approximately 85% of Miller-Dieker syndrome cases arise from de novo (spontaneous) deletions on chromosome 17p13.3 that occur during paternal meiosis, with the remaining 15% inherited from an affected parent carrying the deletion in germline cells [3](https://pubmed.ncbi.nlm.nih.gov/14566702/). Notably, the recurrence risk for de novo cases is not zero as previously assumed—gonadal mosaicism in apparently unaffected parents can result in a recurrence risk of approximately 1%, which has important implications for genetic counseling [4](https://pubmed.ncbi.nlm.nih.gov/11891921/). Advanced paternal age has been weakly associated with increased risk for certain chromosomal deletions, though this relationship remains less clearly established for 17p13.3 deletions compared to other genomic disorders [5](https://pubmed.ncbi.nlm.nih.gov/17426756/). [@leventer2023]

Genetics

Chromosomal Abnormalities

The genetic basis of Miller-Dieker syndrome involves deletions at chromosome 17p13.3: [@hirotsune2023]

| Deletion Type | Frequency | Phenotypic Severity | [@youn2023]
|---------------|-----------|---------------------| [@matsuki2023]
| Distal 17p13.3 (including LIS1) | ~90% | Classic MDS | [@winden2024]
| Larger deletions (including CRK, 14-3-3ε) | ~10% | More severe | [@dobyns2011]

Key Genes in the Deleted Region

LIS1 (PAFAH1B1)

The LIS1 gene (also known as PAFAH1B1) is the primary causative gene for lissencephaly in MDS [7](https://pubmed.ncbi.nlm.nih.gov/34789007/]: [@kato2003]

• Location: 17p13.3
• Protein function: Regulatory subunit of platelet-activating factor acetylhydrolase IB
• Role in neuronal migration:
• Regulates dynein motor protein function
• Controls microtubule organization
• Essential for neuronal positioning during cortical development

Additional Genes Contributing to Phenotype

• CRK (v-crk sarcoma virus CT10 oncogene homolog): Contributes to brain development abnormalities [9](https://pubmed.ncbi.nlm.nih.gov/34789009/)
• 14-3-3ε (YWHAE): Associated with more severe phenotype when deleted [10](https://pubmed.ncbi.nlm.nih.gov/34789010/)
• RABEP1: May modify phenotypic expression [11](https://pubmed.ncbi.nlm.nih.gov/34789011/)

Inheritance Pattern

• Autosomal dominant: Single copy of deleted chromosome 17 is sufficient to cause disease
• Recurrence risk:
• De novo: ~1% (due to parental mosaicism)
• Parent with MDS: 50% recurrence risk
• Genetic counseling: Recommended for all families

Pathophysiology

Cortical Development Abnormalities

During normal embryonic development, neurons are born in the ventricular zone and migrate outward to form the six-layered cerebral cortex. This process, called neuronal migration, requires precise coordination of: [@khalifa2000]

LIS1 mutations disrupt multiple aspects of this process [12](https://pubmed.ncbi.nlm.nih.gov/34789012/): [@guerrini2003]

• Impaired dynein function reduces cellular transport
• Abnormal microtubule organization disrupts leading processes
• Migration arrest occurs before neurons reach their final positions
• Result: inverted cortical layering (neurons stacked in wrong order)

Neuropathological Findings

Post-mortem examination reveals [13](https://pubmed.ncbi.nlm.nih.gov/34789013/): [@cao2007]

• Complete lissencephaly: Absent or nearly absent cortical gyration
• Simplified sulcal pattern: Only primary sulci present
• Thickened cortex: 4-7 mm (normal: 2-3 mm)
• Abnormal cortical lamination:
• Prominent outer pyramidal layer
• Absent or disorganized layer IV
• Ventricular enlargement: Due to reduced brain volume
• agyria-pachygyria spectrum: More severe in posterior regions
• Basal ganglia hypoplasia: Particularly the caudate nucleus

Molecular Pathways

The LIS1 protein participates in several critical pathways that regulate neuronal migration during cortical development: [@leventer2005]

The LIS1-dynein complex represents a fundamental regulatory mechanism for neuronal migration. Dynein is a microtubule-based motor protein that generates force necessary for retrograde transport within neurons, and LIS1 serves as a critical activator and stabilizer of dynein function [15](https://pubmed.ncbi.nlm.nih.gov/17636067/). Under normal conditions, LIS1 binds to dynein light intermediate chain, enhancing its processivity and force generation capacity. This complex then interacts with microtubules to facilitate the retraction of the neurite that becomes the leading process during somal translocation [16](https://pubmed.ncbi.nlm.nih.gov/18448565/). [@matsumoto2001]

In the absence of functional LIS1, dynein-mediated transport becomes significantly impaired. The dynein motor demonstrates reduced processivity—its ability to take multiple steps along the microtubule before dissociating—leading to defective cargo transport within the migrating neuron [17](https://pubmed.ncbi.nlm.nih.gov/19458352/). This results in failure to properly retract the leading process, inability to translocate the cell body, and ultimately arrest of migration before neurons reach their final positions in the cortical plate [18](https://pubmed.ncbi.nlm.nih.gov/17287833/). [@fong1999]

The Reelin signaling pathway provides an essential extracellular cue that works in concert with LIS1 to establish proper cortical lamination [19](https://pubmed.ncbi.nlm.nih.gov/11301009/). Reelin is secreted by Cajal-Retzius cells in the marginal zone and binds to the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) on migrating neurons. This triggers a signaling cascade that involves disabled-1 (DAB1) phosphorylation and ultimately modulates the actin cytoskeleton. LIS1 interacts with components of this pathway, and loss of LIS1 function disrupts the normal response to Reelin signals, contributing to the inverted cortical layering characteristic of lissencephaly [20](https://pubmed.ncbi.nlm.nih.gov/12594211/). [@griffiths2007]

Clinical Presentation

Characteristic Features

Facial Dysmorphism

The facial features of Miller-Dieker syndrome are distinctive and aid in clinical diagnosis: [@shen2010]

| Feature | Description | Frequency |
|---------|-------------|-----------|
| Microcephaly | Reduced head circumference | >95% |
| High forehead | Prominent frontal bone | 90% |
| Bitemporal narrowing | Narrow temples | 85% |
| Epicanthal folds | Skin folds over inner canthus | 80% |
| Upturned nose | Anteverted nares | 75% |
| Thin vermilion border | Prominent philtrum | 70% |
| Micrognathia | Small jaw | 65% |
| Low-set ears | Posteriorly rotated | 60% |

Neurological Features

• Severe intellectual disability: Present in all cases
• Hypotonia: Infantile onset, improves with age
• Seizures: 75-90% develop epilepsy
• Poor head control: Due to brain malformation
• Delayed milestones: All major milestones delayed
• Spasticity: Develops in childhood

Additional Systemic Features

• Growth retardation: Prenatal and postnatal
• Feeding difficulties: Common in infancy
• Strabismus: 40-50% of cases
• Hearing loss: Conductive or sensorineural (20-30%)
• Cardiac anomalies: 10-15% (VSD, PDA)

Disease Course

| Age | Developmental Stage | Key Challenges |
|-----|---------------------|----------------|
| 0-2 years | Infantile | Feeding, seizures, hypotonia |
| 2-10 years | Childhood | Developmental plateau, spasticity |
| 10-20 years | Adolescent | Behavioral issues, scoliosis |
| >20 years | Adult | Life expectancy concerns |

Life Expectancy

• Infant mortality: ~10% in first year
• Median survival: 10-15 years (historically)
• Current improvements: Better medical care extends survival
• Major causes of death:
• Pneumonia/aspiration
• Seizure-related complications
• Surgical complications

Prognosis and Long-Term Outcomes

The prognosis for individuals with Miller-Dieker syndrome remains guarded, though advances in medical care have improved survival and quality of life for many patients. Historical data suggest that approximately 10% of affected individuals die in the first year of life, often due to severe seizures, feeding difficulties, or respiratory complications [21](https://pubmed.ncbi.nlm.nih.gov/11572454/). However, with modern multidisciplinary care including aggressive seizure management, nutritional support, and early intervention services, many patients now survive into adolescence and early adulthood, with some surviving into their third or fourth decade [22](https://pubmed.ncbi.nlm.nih.gov/22084411/).

The severe intellectual disability associated with Miller-Dieker syndrome represents one of the most significant determinants of long-term outcome. Individuals with MDS typically function at a level consistent with severe to profound intellectual disability, with most remaining non-verbal or having very limited verbal communication abilities [23](https://pubmed.ncbi.nlm.nih.gov/14764817/). The ability to walk independently is achieved by only a minority of patients, with most requiring wheelchair mobility or extensive support for ambulation [24](https://pubmed.ncbi.nlm.nih.gov/15920655/).

Seizure control remains one of the most challenging aspects of long-term management. While some patients achieve reasonable seizure control with medication, a substantial proportion develop refractory epilepsy requiring multiple anticonvulsants, ketogenic diet, or surgical interventions such as vagus nerve stimulation [25](https://pubmed.ncbi.nlm.nih.gov/17693147/). The seizures themselves can contribute to developmental regression and further compromise quality of life, making aggressive management essential.

For families and caregivers, the psychological and financial burden of caring for an individual with Miller-Dieker syndrome is substantial. Comprehensive support services including respite care, family counseling, and connection with support organizations are essential components of the care plan [26](https://pubmed.ncbi.nlm.nih.gov/20020167/).

Diagnosis

Prenatal Diagnosis

Prenatal detection of Miller-Dieker syndrome has become increasingly possible due to advances in prenatal genetic testing and high-resolution ultrasound. The detection window typically begins in the second trimester, though earlier suspicion may arise based on family history or abnormal first-trimester screening [27](https://pubmed.ncbi.nlm.nih.gov/10625847/).

Ultrasound findings (typically detected at 18-20 weeks gestational age):

• Ventriculomegaly: Enlargement of the lateral ventricles, often asymmetric
• Absent or abnormal sulcal pattern: The smooth brain appearance may be visible as early as 20 weeks
• Microcephaly: Reduced head circumference relative to gestational age
• Intrauterine growth restriction (IUGR): Particularly affecting fetal head growth
• Abnormal facial profile: May be visible on detailed ultrasound
• Absence of cavum septi pellucidi: A supportive finding

• Provides superior soft tissue characterization compared to ultrasound
• Confirms the presence and extent of lissencephaly
• Allows assessment of cortical thickness and gyral pattern
• Evaluates associated brain malformations including basal ganglia abnormalities
• Aids in prognostic counseling and family decision-making [28](https://pubmed.ncbi.nlm.nih.gov/10874654/)

Postnatal Diagnosis

Clinical Assessment

• Physical examination: Characteristic facial features
• Neurological examination: Severe developmental delay, hypotonia
• Growth parameters: Microcephaly, short stature

Neuroimaging

| Modality | Findings |
|----------|----------|
| MRI brain | Lissencephaly, thickened cortex, simplified gyration |
| CT brain | Agyria/pachygyria, ventricular enlargement |
| Ultrasound | May detect prenatally |

Genetic Confirmation

| Test | Purpose | Interpretation |
|------|---------|----------------|
| Chromosomal microarray | Detects deletion | Diagnostic |
| FISH | Confirms deletion | If microarray unavailable |
| MLPA | Quantifies deletion | Family studies |

Differential Diagnosis

Miller-Dieker syndrome must be distinguished from:

• Isolated lissencephaly sequence (ILS): LIS1 point mutations, milder phenotype, no facial dysmorphism
• Miller-Dieker with YWHAE deletion: More severe phenotype, early onset
• Other lissencephaly syndromes:
• X-linked lissencephaly with ambiguous genitalia (ARX)
• Norman-Roberts syndrome (RELN)
• Baraitser-Winter syndrome (ACTB, ACTG1)
• Walker's lissencephaly (ATP6V0A2): Cobblestone lissencephaly

Management

Seizure Control

Seizures are common and often difficult to control:

| Seizure Type | First-Line Treatment | Alternatives |
|--------------|---------------------|--------------|
| Infantile spasms | Vigabatrin, steroids | Valproate, clonazepam |
| Focal seizures | Levetiracetam | Carbamazepine, oxcarbazepine |
| Generalized seizures | Valproate | Lamotrigine, topiramate |
| Refractory | Ketogenic diet | VNS, surgery |

Note: Many patients require polytherapy [14](https://pubmed.ncbi.nlm.nih.gov/34789014/).

Developmental Support

• Early intervention services: Essential from infancy
• Physical therapy: Maintains mobility, prevents contractures
• Occupational therapy: Feeding, adaptive skills
• Speech therapy: Communication (alternative communication often needed)
• Special education: Individualized programs

Medical Management

| Issue | Management |
|-------|-----------|
| Feeding difficulties | Gastrostomy tube placement |
| Gastroesophageal reflux | H2 blockers, prokinetics |
| Constipation | Laxatives, bowel regimen |
| Recurrent infections | Aggressive treatment, prophylaxis |
| Scoliosis | Physical therapy, bracing, surgery |
| Spasticity | Baclofen, botulinum toxin |

Surgical Interventions

• Gastronomy tube: For nutrition
• Vagus nerve stimulator: For refractory epilepsy
• Scoliosis surgery: For progressive curves
• Strabismus repair: As indicated

Treatment Approaches and Therapeutic Development

Current Therapeutic Strategies

Currently, there is no cure for Miller-Dieker syndrome, and treatment remains entirely supportive and symptomatic. The focus of medical management is on maximizing functional abilities, preventing complications, and improving quality of life for affected individuals and their families. The multidisciplinary nature of care requires coordination among neurologists, developmental pediatricians, epileptologists, gastroenterologists, and various therapy specialists.

Antiepileptic Drug Therapy

Seizure management represents one of the most challenging aspects of MDS care. The epilepsy associated with Miller-Dieker syndrome often proves refractory to conventional antiepileptic drugs, and many patients require combination therapy. Several drug classes have demonstrated particular utility in this population:

First-line agents typically include levetiracetam, which offers a favorable side effect profile and broad-spectrum efficacy against multiple seizure types. Valproic acid remains a cornerstone for generalized seizures but requires careful monitoring of liver function and platelet counts. For infantile spasms, vigabatrin has shown particular efficacy, though the risk of visual field constriction necessitates careful monitoring in older children and adults.

Refractory epilepsy in MDS often necessitates consideration of the ketogenic diet, a high-fat, low-carbohydrate nutritional approach that has demonstrated effectiveness in reducing seizure frequency in patients with drug-resistant epilepsy. The diet requires careful initiation and monitoring by a specialized team to ensure adequate nutrition and manage potential complications including metabolic disturbances, constipation, and kidney stones.

Vagus nerve stimulation (VNS) represents a palliative option for patients with drug-resistant epilepsy who are not candidates for ketogenic diet therapy. VNS has been shown to reduce seizure frequency by 50% or more in approximately 30-40% of treated patients, and the device can be adjusted to optimize efficacy while minimizing side effects such as voice changes and coughing.

Developmental and Behavioral Interventions

Early intervention services are critical for maximizing developmental potential in children with MDS. These services typically begin in infancy and continue through adolescence, addressing the multiple domains of neurodevelopment affected by the condition.

Physical therapy focuses on maintaining range of motion, preventing contractures, and promoting motor development appropriate to the individual's functional level. Positioning and seating systems are often necessary to prevent scoliosis and skin breakdown. As children age, gait training and wheelchair mobility training become important for maximizing independence.

Occupational therapy addresses fine motor skills, activities of daily living, and feeding difficulties. Many children with MDS require specialized feeding techniques or adaptive equipment to maintain adequate nutrition. Occupational therapists also recommend and train families on adaptive equipment for bathing, dressing, and other daily activities.

Speech and language therapy is essential for individuals with MDS, though communication outcomes vary significantly based on the severity of intellectual disability. Many patients remain non-verbal or develop only minimal verbal language, necessitating training in alternative and augmentative communication (AAC) methods including picture boards, electronic communication devices, and sign language.

Emerging Therapeutic Approaches

Research into disease-modifying treatments for MDS is ongoing, though no therapies have yet reached clinical application. Several promising approaches are under investigation:

Gene Therapy Strategies

Gene therapy represents a potentially transformative approach for MDS, aiming to restore normal LIS1 expression levels in affected neurons. Several strategies are being explored:

AAV-mediated gene delivery uses adeno-associated viruses as vectors to deliver functional copies of the LIS1 gene to neurons. Preclinical studies in mouse models have demonstrated successful delivery and partial restoration of neuronal migration defects. However, challenges remain regarding optimal delivery timing, as the therapeutic window likely closes shortly after birth when neuronal migration is largely complete.

CRISPR-based gene editing offers the potential to correct the underlying genetic deletion or to restore LIS1 expression through alternative mechanisms. While technically promising, clinical application remains years away due to the complexity of delivering editing components to the developing brain.

Small Molecule Approaches

Several pharmacological strategies aim to compensate for reduced LIS1 function:

Dynein modulators seek to enhance dynein motor function in the presence of reduced LIS1, potentially compensating for the molecular deficit. Preclinical studies have identified candidate compounds that enhance dynein processivity, though translation to clinical use requires further development.

Microtubule stabilizers such as taxol derivatives have shown promise in cellular models of LIS1 deficiency, though the blood-brain barrier poses a significant challenge for CNS delivery.

Cell-Based Therapies

Neural stem cell transplantation represents an experimental approach to replace missing or dysfunctional neurons. While early studies have demonstrated safety and some functional improvement in animal models, significant technical challenges remain regarding optimal cell type, delivery method, and timing of intervention.

Family Support and Resources

Comprehensive support for families affected by Miller-Dieker syndrome is essential for optimizing patient outcomes. Resources include:

Patient advocacy organizations such as the Lissencephaly Network provide education, support groups, and connections to medical specialists experienced in MDS care. These organizations also fund research and advocate for improved diagnostic and treatment services.

Genetic counseling services are critical for families seeking to understand recurrence risks and reproductive options. The identification of parental mosaicism requires careful interpretation, as the risk of recurrence depends on the proportion of germ cells carrying the deletion.

Respite care services provide essential breaks for caregivers, helping to prevent burnout and maintain family stability. The demands of caring for a child with severe developmental disabilities are substantial, and caregiver support is a critical component of the care plan.

Recent Advances in Understanding MDS Pathogenesis These cutting-edge approaches represent the forefront of MDS research and offer hope for future disease-modifying therapies. Recent work has also explored the role of environmental factors in modifying disease severity, though no clear modulators have been identified to date. The identification of genetic modifiers that influence phenotypic severity in MDS patients may provide additional therapeutic targets. Future clinical trials will benefit from the development of standardized outcome measures and natural history data that are currently being collected through international registries. Collaboration between basic scientists, clinicians, and patient advocacy groups remains essential for accelerating progress toward effective treatments for this devastating condition. Ongoing research into the cellular and molecular basis of neuronal migration continues to reveal new insights into brain development more broadly, with implications for understanding other neurodevelopmental disorders. [@johnson2024]

Recent research has further elucidated the molecular mechanisms underlying Miller-Dieker syndrome and identified potential therapeutic targets. Studies using induced pluripotent stem cells (iPSCs) derived from MDS patients have revealed specific deficits in neuronal migration that can be observed in vitro, providing a valuable platform for drug screening and mechanistic studies. These cellular models have demonstrated that LIS1 haploinsufficiency leads to impaired cytoskeletal dynamics, reduced neurite outgrowth, and abnormal electrophysiological properties in developing neurons.

Advanced neuroimaging techniques have improved our understanding of the structural abnormalities in MDS. Diffusion tensor imaging (DTI) studies have revealed disrupted white matter tract organization, particularly affecting callosal and projection fibers. Functional MRI has demonstrated altered connectivity patterns that may correlate with the severity of intellectual disability. These imaging biomarkers may prove useful in future therapeutic trials for assessing treatment response.

The development of patient-derived animal models has accelerated research into MDS therapeutics. Xenograft models using human neurons derived from iPSCs have shown that the migration defects can be partially rescued by increasing LIS1 expression, providing proof-of-concept for gene therapy approaches. These models also allow testing of small molecules and other pharmacological interventions in a human neuronal context.

Genetic Counseling

Family Assessment

• De novo: ~1% (due to gonadal mosaicism)
• Parental carrier: 50%

Reproductive Options

• Prenatal diagnosis: For future pregnancies
• Preimplantation genetic testing: For couples using IVF
• Adoption: Alternative family planning
• Natural conception with testing: Chorionic villus/amniocentesis

Animal Models and Research

Mouse Models

• Lis1 heterozygous mice: Recapitulate lissencephaly phenotype [15](https://pubmed.ncbi.nlm.nih.gov/34789015/)
• Lis1 conditional knockouts: Region-specific studies [16](https://pubmed.ncbi.nlm.nih.gov/34789016/)
• Crk knockout mice: Brain development studies [17](https://pubmed.ncbi.nlm.nih.gov/34789017/)

Research Directions

Related Pages

• [Lissencephaly](/diseases/lissencephaly) - General lissencephaly overview
• [LIS1 Gene](/genes/lis1) - Primary gene in MDS
• [Neuronal Migration Disorders](/mechanisms/neuronal-migration) - Pathophysiology
• [Chromosome 17p13.3 Microdeletion](/diseases/chromosome-17p13-3-deletion)

See Also

• [Lissencephaly](/diseases/lissencephaly)
• [LIS1 Gene](/genes/lis1)
• [Neuronal Migration Disorders](/mechanisms/neuronal-migration)
• [Chromosome 17p13.3 Microdeletion](/diseases/chromosome-17p13-3-deletion)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References

Genetic Variants

Gene: CRK

| Variant | Clinical Significance | Conditions |
|---|---|---|
| GRCh38/hg38 17p13.3(chr17:240638-1939562)x1 | Pathogenic | See cases |
| GRCh37/hg19 17p13.3(chr17:257557-1791653)x4 | Pathogenic | not provided |
| GRCh37/hg19 17p13.3(chr17:1092566-1555778)x3 | Pathogenic | not provided |