What condition has the following features?

• Gynecomastia

• Small testes

• Tall stature

• Most common sex chromosome aneuploidy

• Low testosterone

• Infertility due to azoospermia

• Intellectual disability and behavioral differences

• Increased cancer risk

Klinefelter syndrome (47, XXY)

Which condition has the following ultrasound findings and associated features?

• Midline defects (clefts, holoprosencephaly)

• Cardiac defects

• Polydactyly

• Rocker bottom feet

• Clenched hands with overlapping fingers

• Thick nuchal translucency

Trisomy 13 (Patau syndrome)

What condition has the following ultrasound findings and associated features?

• Webbed neck

• Increased nuchal translucency (cystic hygroma)

• Horseshoe kidney

• Cardiac defects (i.e. coarctation of the aorta)

• Hydrops

• Short stature

• Widely spaced nipples

• Visio spatial defects

• Delayed puberty/no periods

• Streak gonads

• Infertility

Monosomy X (Turner syndrome, 45,X)

What condition has the following features?

• Females may be taller than average

• Most able to conceive children

• Increased risk of learning disabilities and developmental delays

• Seizures or kidney abnormalities occur in 10%

Triple X syndrome (47, XXX)

Which condition has the following features?

• Extra set of all chromosomes

• Usually results in first trimester miscarriage

• Those that survive are often mosaic and have multiple congenital anomalies and are smaller

Triploidy (69 XXX or XXY)

What are the different causes of triploidy?

2 sperm fertilize 1 egg (most common)

Diploid sperm: placental anomalies, large and cystic, hydatidiform mole

Diploid egg: IUGR, multiple congenital anomalies

What condition has the following ultrasound findings?

• Increased nuchal translucency

• Absent nasal bone

• Cardiac anomalies

• Echogenic bowel

• Echogenic intracardiac focus

With the following features after birth:

• Intellectual disability

• GI anomalies

• Risk for leukemia

• Early onset dementia

Down syndrome aka trisomy 21

What condition has the following features?

• Males may be taller than average

• Usually normal production of testosterone and male sexual development

• Usually fertile

• Increased risk of learning disabilities and developmental delays

• Delayed motor skills

• Tremors, seizures, asthma

• Increased belly fat, macrocephaly, macrodontia

Jacobs syndrome (47, XYY)

Ultrasound findings and associated features include:

• Choroid plexus cysts

• Clenched fists

• Rocker bottom feet

• Cardiac and renal anomalies

• Intrauterine growth restriction

• Thick nuchal translucency

• Hypoplastic nasal bone

Edwards syndrome (trisomy 18)

What condition has the following gene region:

15q11.2-q13

Angelman syndrome

What condition has the following genetic etiologies?

• 5-7 Mb deletion (~70%)

• UBE3A pathogenic variant (11%)

• Paternal UPD (5%)

• Imprinting defect (~4%)

Angelman syndrome (same as Prader-Willi)

What is the gene region for Angelman syndrome?

15q11.2-q13

What are the genetic etiologies of Angelman syndrome?

• 5-7 Mb deletion (~70%)

• UBE3A pathogenic variant (11%)

• Paternal UPD (5%)

• Imprinting defect (~4%)

What condition has the following features?

• Intellectual disability

• Developmental delays

• Gait ataxia

• Happy/excited demeanor (previously referred to as “happy puppet demeanor”)

• Microcephaly

• Seizures

Angelman syndrome

What are the features of Angelman syndrome?

• Intellectual disability

• Developmental delays

• Gait ataxia

• Happy/excited demeanor (previously referred to as “happy puppet demeanor”)

• Microcephaly

• Seizures

What are the ultrasound findings and features of Trisomy 13 (Patau syndrome)?

• Midline defects (clefts, holoprosencephaly)

• Cardiac defects

• Polydactyly

• Rocker bottom feet

• Clenched hands with overlapping fingers

• Thick nuchal translucency

What are the ultrasound findings and features of Monosomy X?

• Webbed neck

• Increased nuchal translucency (cystic hygroma)

• Horseshoe kidney

• Cardiac defects (i.e. coarctation of the aorta)

• Hydrops

• Short stature

• Widely spaced nipples

• Visio spatial defects

• Delayed puberty/no periods

• Streak gonads

• Infertility

What are the features of Triple X syndrome (47, XXX)?

• Females may be taller than average

• Most able to conceive children

• Increased risk of learning disabilities and developmental delays

• Seizures or kidney abnormalities occur in 10%

What are the features of Triploidy (69 XXX or XXY)?

• Extra set of all chromosomes

• Usually results in first trimester miscarriage

• Those that survive are often mosaic and have multiple congenital anomalies and are smaller

What are the ultrasound findings and features of T21?

Ultrasound findings:

• Increased nuchal translucency

• Absent nasal bone

• Cardiac anomalies

• Echogenic bowel

• Echogenic intracardiac focus

Features after birth:

• Intellectual disability

• GI anomalies

• Risk for leukemia

• Early onset dementia

What are the features of Klinefelter syndrome?

• Gynecomastia

• Small testes

• Tall stature

• Most common sex chromosome aneuploidy

• Low testosterone

• Infertility due to azoospermia

• Intellectual disability and behavioral differences

• Increased cancer risk

What are the features of Jacobs syndrome (47, XYY)?

• Males may be taller than average

• Usually normal production of testosterone and male sexual development

• Usually fertile

• Increased risk of learning disabilities and developmental delays

• Delayed motor skills

• Tremors, seizures, asthma

• Increased belly fat, macrocephaly, macrodontia

What are the features of Edward’s syndrome (T18)?

• Choroid plexus cysts

• Clenched fists

• Rocker bottom feet

• Cardiac and renal anomalies

• Intrauterine growth restriction

• Thick nuchal translucency

• Hypoplastic nasal bone

What condition has the following gene region:

11p15.5, chr 7

Russell Silver syndrome

What is the gene region for Russell Silver syndrome?

11p15.5, chr 7

What condition has the following genetic etiologies (found in 60% of cases):

• Imprinting defect at 11p15.5 (35-50%)

• Maternal UPD7 (~10%)

• Del/dup involving imprinting center at 11p15.5 or chr7 (rare)

• Variant in CDKN1C, IGF2, or other gene near 11p15.5 (rare)

Russell Silver syndrome

What are the genetic etiologies of Russell Silver syndrome?

Found in 60% of cases:

• Imprinting defect at 11p15.5 (35-50%)

• Maternal UPD7 (~10%)

• Del/dup involving imprinting center at 11p15.5 or chr7 (rare)

• Variant in CDKN1C, IGF2, or other gene near 11p15.5 (rare)

What percentage of cases is a genetic etiology found for Russell Silver syndrome?

~60%

What condition has the following features?

• Body asymmetry

• Triangular facies

• Fifth finger clinodactyly

• Relative macrocephaly at birth

• Frontal bossing

• Micrognathia

• Short stature

Russell Silver syndrome

What are the features of Russell Silver syndrome?

• Body asymmetry

• Triangular facies

• Fifth finger clinodactyly

• Relative macrocephaly at birth

• Frontal bossing

• Micrognathia

• Short stature

What condition has the following gene region:

15q11.2-q13

Prader Willi syndrome (same as Angelman)

What is the gene region for Prader-Willi syndrome?

15q11.2-q13

What condition has the following genetic etiologies?

• 4-6 Mb deletion (~70%)

• Maternal UPD (~25%)

• <1% imprinting defect

Prader-Willi syndrome

What are the genetic etiologies for Prader-Willi syndrome?

• 4-6 Mb deletion (~70%)

• Maternal UPD (~25%)

• <1% imprinting defect

What condition has the following features?

• Hypotonia

• Feeding issues in infancy followed by excessive eating and obesity in childhood

• Cognitive impairment

• Behavioral differences (i.e. tantrums, stubbornness, OCD)

• Hypogonadism

• Prader-Willi syndrome

What are the features of Prader-Willi syndrome?

• Hypotonia

• Feeding issues in infancy followed by excessive eating and obesity in childhood

• Cognitive impairment

• Behavioral differences (i.e. tantrums, stubbornness, OCD)

• Hypogonadism

What condition has the following gene region:

11p15.5

Beckwith-Wiedemann syndrome

What is the gene region for Beckwith-Wiedemann syndrome?

11p15.5

What condition has the following genetic etiologies?

• Important genes: IGF2, H19, CDKN1C

• Imprinting defect called imprinting center 1&2 (~55%)

• UPD (20%)

• CDKN1C variant (~10%)

• Micro del/dup (~10%)

Beckwith-Wiedemann syndrome

What are the genetic etiologies of Beckwith-Wiedemann syndrome?

• Important genes: IGF2, H19, CDKN1C

• Imprinting defect called imprinting center 1&2 (~55%)

• UPD (20%)

• CDKN1C variant (~10%)

• Micro del/dup (~10%)

What condition has the following features?

• Omphalocele

• Macroglossia (abnormal enlargement of the tongue)

• Wilms tumor

• Body asymmetry

• Neonatal hypoglycemia

• Macrosomia

Beckwith-Wiedemann syndrome

What are the features of Beckwith-Wiedemann syndrome?

• Omphalocele

• Macroglossia (abnormal enlargement of the tongue)

• Wilms tumor

• Body asymmetry

• Neonatal hypoglycemia

• Macrosomia

F5 gene condition?

Factor V Leiden

What is the gene for Factor V Leiden?

F5

Factor V Leiden inheritance?

Autosomal dominant

What condition has the following features?

• Increased clotting

• Risk of deep vein thrombosis

  • Homozygotes have a higher risk than heterozygotes

• Increased risk of recurrent pregnancy loss

Factor V Leiden

What are the features for Factor V Leiden?

• Increased clotting

• Risk of deep vein thrombosis

  • Homozygotes have a higher risk than heterozygotes

• Increased risk of recurrent pregnancy loss

What condition has the following genes?

HBA1, HBA2

Alpha thalassemia

What are the genes for alpha thalassemia?

HBA1, HBA2

What is the inheritance of alpha thalassemia?

Autosomal recessive

What condition is this describing?

• Typically 4 alpha globin genes present

• Deletions in these can cause different levels of disease

  • Can have point mutations but deletions are most common (90%)

• Complete blood count may show low MCV, while hemoglobin electrophoresis is normal

  • Rule out low iron, then molecular testing for alpha thal gene variants (start with del/dup analysis and then sequencing)

Alpha thalassemia

HFE gene condition?

HFE-associated hereditary hemochromatosis

Fe = Iron!

What is the inheritance of HFE-associated hereditary hemochromatosis?

Autosomal recessive

Low penetrance

What condition has the following features?

• High iron absorption

• Excess iron storage in the liver, skin, pancreas

• Pain, weakness, lethargy

• Males more severely affected as females lose some excess iron during menstruation

HFE-associated hereditary hemochromatosis

Fe = Iron!

What are the features of HFE-associated hereditary hemochromatosis?

• High iron absorption

• Excess iron storage in the liver, skin, pancreas

• Pain, weakness, lethargy

• Males more severely affected as females lose some excess iron during menstruation

F8 (factor 8) gene condition?

Hemophilia A

F9 (factor 9) gene condition?

Hemophilia B

What gene is associated with hemophilia A?

F8

What gene is associated with hemophilia B?

F9

What is the inheritance of hemophilia A/B?

X-linked

Female carriers are typically unaffected, however, they may exhibit mild symptoms due to skewed X inactivation

What are the features of hemophilia A/B?

• Excessive or prolonged bleeding

• Nose bleeds

• Excessive bruising

What condition has the following features?

• Excessive or prolonged bleeding

• Nose bleeds

• Excessive bruising

Hemophilia A/B

HBB gene condition?

Beta thalassemia

What is the gene for beta thalassemia?

HBB

Beta thalassemia features

• Carriers can have mild anemia, called thalassemia minor

• Those affected can have varying levels of symptoms

  • Beta thalassemia major = severe microcytic anemia, mild jaundice, hepatosplenomegaly

    • Require regular blood transfusions

  • Beta thalassemia intermedia = similar, milder symptoms

• The presence of beta thalassemia and sickle cell together can be more severe, depending on the specific mutations

What lab results indicate beta thalassemia?

• Complete blood count:

  • Low MCV

• Hemoglobin electrophoresis:

  • High Hb A2

  • High Hb F

HMBS gene condition?

Acute intermittent porphyria

What is the gene for acute intermittent porphyria?

HMBS

What is the inheritance for acute intermittent porphyria?

Autosomal dominant

What condition has the following features?

• Red or brown urine

• Abdominal pain

• Gastrointestinal issues

• Symptoms appear quickly and last a short time

Acute intermittent porphyria

What type of condition is acute intermittent porphyria?

Metabolic

What are the features of acute intermittent porphyria?

• Red or brown urine

• Abdominal pain

• Gastrointestinal issues

• Symptoms appear quickly and last a short time

GALC gene condition?

Krabbe disease

What is the gene for Krabbe disease?

GALC

What is the inheritance for Krabbe disease?

Autosomal recessive

What condition has the following features?

• GALC enzyme deficiency

• Extreme irritability and spasticity

  • Tip: think crabby

• Developmental delay

• Death before age 2 for most individuals

Krabbe disease

What are the features of Krabbe?

• GALC enzyme deficiency

• Extreme irritability and spasticity

  • Tip: think crabby

• Developmental delay

• Death before age 2 for most individuals

What type of condition is Krabbe disease?

Metabolic

DHCR7 gene condition?

7-dehydrocholesterol reductase deficiency

Smith-Lemli-Opitz syndrome

What is the gene for Smith-Lemli-Opitz syndrome?

DHCR7

What is the inheritance of Smith-Lemli-Opitz syndrome?

Autosomal recessive

Smith-Lemli-Opitz flag on quad maternal serum screen?

Low estriol (<0.15 MoM)

What condition has the following features?

• XY have ambiguous genitalia

• Midline anomalies (holoprosencephaly)

• 2-3 syndactyly

• Polydactyly

• Intrauterine growth restriction

• Microcephaly

• Intellectual disability

Smith-Lemli-Opitz syndrome

What are the features of Smith-Lemli-Opitz syndrome?

• XY have ambiguous genitalia

• Midline anomalies (holoprosencephaly)

• 2-3 syndactyly

• Polydactyly

• Intrauterine growth restriction

• Microcephaly

• Intellectual disability

What type of condition is Smith-Lemli-Opitz syndrome?

Metabolic

ASPA gene condition?

Canavan disease

What is the gene for Canavan disease?

ASPA

What is the inheritance for Canavan disease?

Autosomal recessive

What is the AJ carrier frequency for Canavan disease?

1/40

What condition has the following features?

• Type of leukodystrophy that damages the ability of nerve cells to communicate

• Mostly infantile onset

• Missing milestones

• Macrocephaly

• Seizures

• Feeding and sleep issues

Canavan disease

What are the features of Canavan disease?

• Type of leukodystrophy that damages the ability of nerve cells to communicate

• Mostly infantile onset

• Missing milestones

• Macrocephaly

• Seizures

• Feeding and sleep issues

What type of condition is Canavan disease?

Metabolic

SERPINA1 gene condition?

Alpha-1-antitrypsin deficiency

What is the gene for Alpha-1-antitrypsin deficiency?

SERPINA1

What is the inheritance for Alpha-1-antitrypsin deficiency?

Autosomal recessive

What condition has the following features?

• Adult onset lung and liver disease (10%)

  • Symptoms of lung disease normally develop ~25-50 years of age

  • 15% of adults develop liver damage

    • Signs include swollen abdomen and jaundice

  • In rare cases, may develop panniculitis, as skin condition that results in hardened skin and painful lumps or patches

Alpha-1-antitrypsin deficiency

What are the features of Alpha-1-antitrypsin deficiency?

• Adult onset lung and liver disease (10%)

  • Symptoms of lung disease normally develop ~25-50 years of age

  • 15% of adults develop liver damage

    • Signs include swollen abdomen and jaundice

  • In rare cases, may develop panniculitis, as skin condition that results in hardened skin and painful lumps or patches

Condition with genes BRAF, MAP2K1/2, KRAS?

Cardio-facio-cutaneous syndrome

What are the gens for cardio-facio-cutaneous syndrome?

BRAF, MAP2K1/2, KRAS