Paula Goldenberg, MD, MSW, MSCE Common Genetic Disorders Medical Genetics in Child Neurology Massachusetts General Hospital September 6, 2017 Disclosure

• I am a scientific and clinical advisor for the International 22q11.2 Foundation • Otherwise no conflicts to disclose List common genetic conditions with chromosomal basis

List common genetic syndromes Objectives that may be diagnosed with microarray testing Discuss common genetic disorders typically identified with molecular genetic testing There is a lot of genetics in neurology, and neurologic features in genetic syndromes! This meeting • Neurometabolic Disorders • Ataxias • covers several Neuronal Ceroid Lipofuscinosis • Dystonias • Tuberous Sclerosis • Autism other genetic • Neurofibromatosis conditions • Neuromuscular Disorders • Inherited Neuropathiies • Mitochondrial Disorders • Angelman syndrome • 15q Duplication syndrome • Cerebral dysgenesis • Leukodystrophies and hypomyelinating disorders We will cover 12 common genetic syndromes

• Down syndrome • Cri du Chat syndrome • Trisomy 13 • Fragile X • Trisomy 18 • Rett syndrome • Williams syndrome • PTEN-associated autism • Smith-Magenis syndrome • Sotos syndrome • 22q11 deletion syndrome • Prader-Willi syndrome

Developmental delay, autism ACMG (2013):

Tier 1: Microarray and Fragile X

Tier 2: ••MECP2 in girls, or boys if phenotype is suggestive ••PTEN if HC >2.5 SD ••Brain MRI if specific indicators (microcephaly, regression, seizures, hx of stupor/coma)

Genetic screening for patients with autism or developmental delay Common Chromosomal Syndromes

Down syndrome

Trisomy 13

Trisomy 18 Chromosomal aneuploidy

• Missing or extra chromosome • Best test for evaluating is a chromosome study not microarray • Microarray may not detect trisomy vs. unbalanced Robertsonian translocation • High recurrence risk if a parent has a balanced translocation Down syndrome

1 in 700 births Neurologic features of Down syndrome

• Hypotonia • Developmental delay • Intellectual disability • Autism • Epilepsy • Early onset Alzheimer Dementia • West syndrome: perhaps 5% have Down syndrome1 • Sleep apnea

1Samaneechai O, et al. Treatment outcomes of West Syndrome in infants with Down syndrome. Pediatr Neurol. 2013 Jan;48(1):42-7. Acute Cognitive Regression

• Rarely reported • Recent retrospective case series of 30 patients (age 11-30y) • Onset age 20 years (mean 18y in girls 21y in boys) • May be associated with a trigger event • Change of school • Awareness of disability • Marriage of brother or sister • Assault • Illness or death of friend or family • Overstimulation

Mircher C, et al. Acute regression in young people with Down syndrome. Brain Sci 2017; ePub Clinical presentation

• Mood: Depression, anxiety • Behavior: Apathy, catatonia, self-injury, aggression • Thought: Delusion, stereotypy, inappropriate laughter • ADLs: intact, partial regression, or total regression • Language: intact, partial regression, or mutism • Thyroid, EEG, and brain MRIs are typically normal • Half did not recover, 43% partially recover, 10% fully recover

Mircher C, et al. Acute regression in young people with Down syndrome. Brain Sci 2017; ePub

Trisomy 13 Patau Syndrome • Approximately 1 in 16,000 births • Increased with advanced maternal age • Chromosome study to detect Robertsonian translocation • Microphthalmia, coloboma • Deafness • Cleft lip and/or cleft palate • Aplasia cutis • VSD (80%) Neurologic aspects of Trisomy 13

• Holoprosencephaly • Forebrain, olfactory, optic nerves • Motor seizures with hypsarrhythmia pattern • Apnea in early infancy • Severe intellectual disability • Microcephaly • Hyper- or hypotonia

Trisomy 18 Edwards Syndrome

• More common than trisomy 13 • 1 in 6,000 live births • Increased risk with older mothers • Chromosome study for translocations • Polyhydramnios • IUGR, feeding problems • Hernias (inguinal, umbilical, diastasis recti) • Limited hip abduction • VSD Trisomy 18 Neurologic conditions • Choroid plexus cyst • 5% have brain abnormalities • cerebellar hypoplasia, • agenesis of corpus callosum, • microgyria, • hydrocephalus • myelomeningocele • Hypotonia (infants)-->Hypertonia • Central apnea • Seizures • Intellectual disability Cereda A, Carey JC. The trisomy 18 syndrome. Orphanet J Rare Dis 2012; 7:81. https://www.researchgate.net/figure/7720371_fig1_Fig-1-Magnetic-resonance-image-in-a-4-year-old-girl-with-trisomy-18-showing-cerebellar

Common conditions found on microarray testing

Cri du Chat syndrome (5p deletion) Williams syndrome Smith-Magenis syndrome 22q11 deletion syndrome Prader-Willi syndrome 5p deletion syndrome Cri-du-Chat syndrome

• 1:15,000-50,000 newborns • 85% de novo (80% paternal) • 15% due to paternal translocation • Low birth weight, slow growth (52-70%) • Cat-like cry • Laryngeal abnormality • Mild to profound intellectual disability • Hypotonia • Ophthalmologic features 46%: refraction errors, strabismus, cataracts, optic nerve abnormalities • ADHD Severity depends on deletion location on chromosome 5p • https://www.youtube.com/watch?v=TYQrzFABQHQ

You Tube audio of the high pitched cry “Gid- Cri du Chat” 7q11.23 deletion Williams syndrome

• 1 in 7500-10,000 • Most are de novo • There are some familial cases • Features are not obvious in newborns • Failure to thrive • Supravalvular aortic stenosis, branch PA stenosis, PS, septal defects, renal artery stenosis • Friendliness, empathy • “Cocktail party” personality • Hypercalcemia • CV collapse with anesthesia • Including those that don’t have heart defects • Recommend cardiac anesthesiologist Neurologic and Psychiatric features of Williams syndrome • Anxiety • 50% need treatment for anxiety or • Phobias, fears ADHD • Generalized anxiety • ADHD • Mild to severe intellectual disability • Visuospatial deficits • Relative strength with verbal skills • Love of Music (Berkshires Music Academy: 1st year 85% had Williams) • Hyperacusis 17p11.2 deletion Smith-Magenis Syndrome

• 1 in 25,000 • De novo deletion • One mother mosaic for deletion • RAI1 mutation (in deletion region) • Can be mistaken for Down syndrome in infants • Retinoic Acid Inhibitor 1 accounts for some but not all SMS findings • Often small deletions causing frameshift • SCA2 is caused by CAG repeats of RAI1 (allelic) Smith-Magenis syndrome Neurologic and Psychiatric Features

• Infantile hypotonia • Mild to profound ID • Hoarse voice • Delayed sleep onset, frequent night waking, sleepiness during the day • Circadian disturbance • Self-injury • Head banging • Wrist biting • Onychotillomania • Polyembolokoilamania • Aggression • Insensitivity to pain • Seizures (25%) and abnormal EEGs (50%) • Ventriculomegaly (>50%)

22q11 deletion syndrome

• 1:2,000-4,000 births • Possibly 1:1,000 pregnancies • de novo (90%) or familial (10%) • 5% atypical deletions (negative FISH) • Wide phenotype • No genotype-phenotype correlation • Conotruncal cardiac defects (75%) • Hypoparathyroidism (50-60%, usually in infancy) • Cleft palate, cleft lip, VPI • Thymic hypoplasia 22q11 deletion syndrome Neurologic and psychiatric aspects

• Average borderline IQ with wide distribution • Nonverbal learning disability • Hypotonia • Seizures • Asymmetric crying facies (absent depressor angularis oris) • Cayler cardiofacial syndrome • Cranial nerve dysfunction and aspiration • Polymicrogyria • Anxiety and Depression • Risk of psychosis: approx 25% • At the same time, many young adults go to college and graduate school Patient 1: 4mo “Right Handed”

Extensive right frontal, parietal and temporal polymicrogyria

T2 Axial T1 Coronal T1 Sagittal FLAIR Sagittal Right hemisphere Patient 2: 16m

Bilateral frontal, left parietal, and left temporal involvement

T1 axial T1 axial T2 Coronal T1 Sagittal Left Hemisphere 22q11 deletion syndrome

• Consider microarray for a patient with unilateral or bilateral PMG • Seizures in infancy—if hypocalcemic consider 22q11 deletion syndrome • Asymmetric crying facies: consider microarray testing 15q11.2 Prader-Willi syndrome

• 1 in 10,000-30,000 • Paternal deletion 65-75% • Maternal UPD 20-30% • Imprinting Center defect rare • For some defects need to rule out balanced translocation in parents • Phases of feeding concerns • Normal prenatal growth • Newborns: low muscle tone, poor suck, tube feeding • 2-4.5 years: increased interest in food, crossing percentiles • 8y-adulthood: intense and relentless food seeking (locked food access) • Some adults become able to detect satiety Easiest option! Do methylation PCR and send patients to genetics if positive

Features of PWS

• Hyperphagia: Food-seeking behavior, with hoarding or foraging for food, eating of inedibles, and stealing of food or money to buy food, are common • Ghrelin levels are low • Short stature, small hands and feet, growth hormone deficiency Prader Willi Syndrome Neurologic and Psychiatric features • Delayed milestones (sit 12m, walk 24 mo, delayed language) • Moderate ID 20% • Mild intellectual disability 40%, • borderline/low avg 20% • Sleep: Central and obstructive sleep apnea, altered sleep architecture, ↓REM • Behavior problems 70%-90% (suggestive of ASD in 19%) • Temper tantrums • Stubbornness • Controlling and manipulative behavior • Compulsivity • Difficulty with change in routine • ADHD • Psychosis in 10-20% and more common in those with UPD • Seizures 10-20% Common Molecular Syndromes Fragile X Rett Syndrome PTEN Sotos Syndrome FMR1 Fragile X syndrome

• 1: 3600-4000 Males • 1:4000-6000 Females • >200 CGG repeats of FMR1 • Question: Can Fragile X be diagnosed with sequencing FMR1? • Testing with PCR or Southern Blot • Only a small minority have mutations • Males with full mutation • Intellectual Disability (Moderate to Severe) • Autism • Seizures • ADHD • Females with full mutation • Are fertile • May have learning disability • 1/3 have intellectual disability • Anxiety Complicated Discussions

• Intermediate can expand to premutation (mother to child) • Premutation • Premature ovarian insufficiency • Fragile X Ataxia Tremor syndrome • Can expand to full mutation (mother to child) • Fragile X carrier screening of preconception/pregnant women more commonly currently • Women with premutation/infertility • What if you make a diagnosis and parents say they are not having more children? Why test parents?

• Recurrence Risk: accidents happen • Often additional family members with Fragile X may be diagnosed • 176 probands with Fragile X in Clinic • 227 with full mutation (219 male, 8 female) • 558 with premutation (59 male, 499 female) • On average 5 more family members identified • Family members can have preconception testing or pregnancy options

Visootsak J, et al. Climbing the branches of a family tree: diagnosis of Fragile X syndrome. J Pediatr 2014;164(6): 1292-5. MECP2, Rett syndrome

• 1 in 8500 females, by age 15y • >99% de novo • Rarely mother may carry the mutation with skewed X- inactivation • X-linked dominant • Liveborn males have severe neonatal encephalopathy • Death in early childhood (age 2y) • Classic Rett (females) • Normal development to 6-18 months • Developmental stagnation • Regression of language and motor skills • Repetitive, stereotypic hand motions • Fits of screaming and crying • Autistic features • Panic attacks • Bruxism • Episodic apnea and/or hyperpnea • Gait ataxia • Tremors • Seizures (90%) • Postnatal microcephaly Variant/Atypical Rett

• Most severe form: no period of grossly normal development occurs • Congenital hypotonia and infantile spasms • Milder form: girls have less dramatic regression, milder ID • Gradual regression that begins after the third year, lose purposeful hand use, and develop seizures • retain some speech and the ability to walk • Variant/Atypical Rett can be associated with MECP2, FOXG1 and CDKL5 mutations Rett syndrome

• 1.5% of patients with negative testing for Angelman can have MECP2 mutations • Adulthood: long QT and ECG abnormalities, ?increased risk of sudden death Frontal and profile views of subject two with a PTEN mutation (D252G) at 3.5 years of age showing macrocephaly.

M G Butler et al. J Med Genet 2005;42:318-321

©2005 by BMJ Publishing Group Ltd PTEN-associated autism with macrocephaly

• Possibly 1% of children with autism have PTEN mutations • De novo or familial • Prevalence 1.5 in 10,000? • Head circumference average 4 SD above the mean • Allelic with • Bannayan-Riley-Ruvalcaba Syndrome • Cowden syndrome: an adult cancer risk syndrome • Due to this condition being allelic with Cowden syndrome: • periodic screening for breast, thyroid, renal and endometrial cancers starting at age 18 Sotos syndrome NSD1

• 1 in 10,000-14,000 • Macrocephaly with prenatal onset • Large hands and feet • Advanced bone age • “Sotos-like syndrome” associated with NFIX Sotos syndrome Neurologic and psychiatric findings

• IQ 40-129 mean 78 • Delayed milestones: sit at 9m, walk at 17m, some words 25m • Autism • Seizures • Behavior problems: social skill problems, aggressiveness, tantrums • Immaturity

MRI findings can include ventriculomegaly, complete or partial agenesis of the corpus callosum, supratentorial extra cerebral fluid spaces including the posterior fossa Broad review of 12 high-yield, common syndromes

• Chromosomal • Down syndrome • Trisomy 13 and 18 • Copy number variants (all deletions) • Cri-du-chat • Williams syndrome • Smith-Magenis • Prader-Willi • 22q11 deletion • Molecular • Fragile X • Rett • PTEN • Sotos Many thanks for your kind attention!