ABGC 100 Genetic Conditions- Solved
22q11.2 (Velo-cardio-facial syndrome, DiGeorge syndrome) - ANSWER-Microdeletion,
transmitted as dominant trait
**90% de novo, 3Mb common deletion**
1/4,000 - 1/6,000
CP (**NO CL**), conotruncal cardiac malformations, Absence of parathyroids
(**HYPOcalcemia**)
**Thymus aplasia (immunodeficiency)**
LD and psychiatric disorders
Germline mosaicism possible
47, XXX - ANSWER-Nondisjunction; some have 3+ X
1 in 1,000
Fertile
Cognitive impairment
Tall stature
Recurrence rare but may happen
47, XXY (Klinefelter) - ANSWER-Nondisjunction; may have additional X chr
1/500 - 1/1,000
May fail to develop 2ndary sex characteristics (tx testosterone)
Small testes with few or no sperm
Learning disabilities
Recurrence is rare but may happen
47, XYY (Jacob's) - ANSWER-XYY karyotype due to nondisjunction
1 in 1,000
Fertile with LD and behavioral concerns
Tall stature
Recurrence is rare
Achondroplasia - ANSWER-De novo (80%) AD
**GOF; FGFR3**
Nucleotide 1138; G to A or C
Both cause the same amino acid change in codon 308 and lead to constitutive
activation of the receptor
1/15,000 - 1/40,000
Shortening of limbs due to premature differentiation of cartilage in the growth plate into
bone
Frontal bossing and midface hypoplasia
Lumbar lordosis
Extreme short stature
Normal intelligence
,Respiratory function may be compromised by obstructive apnea and brainstem
compression
Hydrocephalus can occur due to obstruction of the sigmoid sinus
Monitoring for brainstem or spinal cord compression and surgery if necessary
Acute intermittent porphyria - ANSWER-AD
Mutation in HMBS gene, encoding porphobilinogen deaminase
1-2/100,000 in Europe, 1/10,000 in Sweden
Intermittent episodes of abdominal pain, nausea, vomiting, abdominal distention,
constipation or diarrhea
Progressive peripheral neuropathy leading to weakness
Attacks precipitated by exposure to specific environmental agents, including alcohol and
many medications
Avoidance of exposure to inciting agents; acute attacks treated with intravenous
dextrose and hemin
Adrenoleukodystrophy/peroxisomal disorders - ANSWER-XLR with variable expression
ALD (1/20,000) results from mutation in ABCD1 gene
Childhood form - affected boys manifest progressive learning and behavioral problems,
seizures, impaired adrenocortical function
Later onset adrenomyeloneuropathy - progressive gait disorder, loss of sphincter
control, and adrenocortical dysfunction
Other variations are seen, such as isolated adrenal insufficiency
**Diagnosis is based on MRI finding of symmetrical enhanced T2 signal in white matter
in parieto-occipital region and finding of elevated plasma VLCFAs**
Corticosteroid replacement therapy and BMT
**At risk family members should have plasma VLCFA**
Albinism (oculocutaneous albinism) - ANSWER-Genetically heterogeneous, AR or XL
OCA1, due to mutation in the OCA1 gene, which encodes the enzyme tyrosinase;
1/40,000
Failure of conversion of tyrosine to melanin
OCA2, due to mutation in the OCA2 gene that encodes the P protein; **higher
frequency in Africans**
XL form causes ocular albinism (XLOA), due to mutation in the GPR143 gene involved
in melanogenesis in the iris and retina; 1/60,000 males
Deficiency or lack of melanin pigment in skin, hair, and eyes
Risk of sunburn and **skin cancer**
Abnormal ocular development with poor visual acuity, nystagmus, lack of binocular
vision and **sensitivity to bright light**
Alkaptonuria - ANSWER-AR
Mutation in gene HGD, which encodes homogentisic acid oxidase
Urine that darkens over time after voiding
Deposition of homogentisic acid in connective tissue similarly leads to darkening
Arthritis, particularly of the spine, develops beginning in the 3rd decade
, Kidney dysfunction
Clinical trials testing nitisinone, which is an inhibitor of 4- hydroxylphenylpyruvate
dioxygenase, the enzyme that produces homogentisic acid
Alzheimer disease - ANSWER-Multifactorial; EOAD is AD with mutations in the genes
PSEN1 > APP > PSEN2
Encoding presenilin-1, amyloid beta A4 protein and presenilin-2, respectively
e4 allele at APOE locus is a risk factor
Upwards of 5% of individuals over 70 years of age have signs of AZD or dementia
Less than 2% of cases are due to single gene mutations
First-degree relatives face 20-25% risk of developing AZD
Androgen insensitivity syndrome - ANSWER-XLR
Some carriers will manifest due to nonrandom X chr inactivation
1/20,000 - 1/50,000
Mutation in AR gene, which encodes the androgen receptor
**Those with complete insensitivity have normal female external genitalia**
Undescended testes
Lack uterus and Fallopian tubes due to action of Mullerian-inhibiting substance
Those with partial insensitivity have some degree of masculinization of the external
genitalia, and may present with ambiguous genitalia
**Gonadectomy is performed after puberty to prevent gonadoblastoma**
Vaginal dilation
Sex assignment and management is a complex issue
Follow with surgical, endo, genetic and psych
Angelman syndrome - ANSWER-Genomic imprinting disorder
68% Deletion of the maternal 15q11.2-q13 region
11% **UBE3A** gene mutation (AD)
7% Paternal UPD of chr 15
3% Small imprinting region deletions (AD)
1/12,000 - 1/20,000
Severe DD, seizures, hyperactivity, abnormal gait
Recurrence is rare
Ataxia - ANSWER-Genetically heterogeneous; most forms AD
Friedreich ataxia is AR; FXN gene (frataxin)
**GAA triplet repeat expansion within an INTRON**
Normal alleles contain 5 - 33 repeats
Permutation alleles 33 - 65 repeats
Borderline alleles 44-66 repeats
Full penetrance disease alleles 66-1700 repeats
Hereditary ataxia syndromes may manifest as pure ataxia or ataxia in association with
other symptoms
Friedreich ataxia usually has **onset in late childhood or adolescence**, although later
onset may occur
22q11.2 (Velo-cardio-facial syndrome, DiGeorge syndrome) - ANSWER-Microdeletion,
transmitted as dominant trait
**90% de novo, 3Mb common deletion**
1/4,000 - 1/6,000
CP (**NO CL**), conotruncal cardiac malformations, Absence of parathyroids
(**HYPOcalcemia**)
**Thymus aplasia (immunodeficiency)**
LD and psychiatric disorders
Germline mosaicism possible
47, XXX - ANSWER-Nondisjunction; some have 3+ X
1 in 1,000
Fertile
Cognitive impairment
Tall stature
Recurrence rare but may happen
47, XXY (Klinefelter) - ANSWER-Nondisjunction; may have additional X chr
1/500 - 1/1,000
May fail to develop 2ndary sex characteristics (tx testosterone)
Small testes with few or no sperm
Learning disabilities
Recurrence is rare but may happen
47, XYY (Jacob's) - ANSWER-XYY karyotype due to nondisjunction
1 in 1,000
Fertile with LD and behavioral concerns
Tall stature
Recurrence is rare
Achondroplasia - ANSWER-De novo (80%) AD
**GOF; FGFR3**
Nucleotide 1138; G to A or C
Both cause the same amino acid change in codon 308 and lead to constitutive
activation of the receptor
1/15,000 - 1/40,000
Shortening of limbs due to premature differentiation of cartilage in the growth plate into
bone
Frontal bossing and midface hypoplasia
Lumbar lordosis
Extreme short stature
Normal intelligence
,Respiratory function may be compromised by obstructive apnea and brainstem
compression
Hydrocephalus can occur due to obstruction of the sigmoid sinus
Monitoring for brainstem or spinal cord compression and surgery if necessary
Acute intermittent porphyria - ANSWER-AD
Mutation in HMBS gene, encoding porphobilinogen deaminase
1-2/100,000 in Europe, 1/10,000 in Sweden
Intermittent episodes of abdominal pain, nausea, vomiting, abdominal distention,
constipation or diarrhea
Progressive peripheral neuropathy leading to weakness
Attacks precipitated by exposure to specific environmental agents, including alcohol and
many medications
Avoidance of exposure to inciting agents; acute attacks treated with intravenous
dextrose and hemin
Adrenoleukodystrophy/peroxisomal disorders - ANSWER-XLR with variable expression
ALD (1/20,000) results from mutation in ABCD1 gene
Childhood form - affected boys manifest progressive learning and behavioral problems,
seizures, impaired adrenocortical function
Later onset adrenomyeloneuropathy - progressive gait disorder, loss of sphincter
control, and adrenocortical dysfunction
Other variations are seen, such as isolated adrenal insufficiency
**Diagnosis is based on MRI finding of symmetrical enhanced T2 signal in white matter
in parieto-occipital region and finding of elevated plasma VLCFAs**
Corticosteroid replacement therapy and BMT
**At risk family members should have plasma VLCFA**
Albinism (oculocutaneous albinism) - ANSWER-Genetically heterogeneous, AR or XL
OCA1, due to mutation in the OCA1 gene, which encodes the enzyme tyrosinase;
1/40,000
Failure of conversion of tyrosine to melanin
OCA2, due to mutation in the OCA2 gene that encodes the P protein; **higher
frequency in Africans**
XL form causes ocular albinism (XLOA), due to mutation in the GPR143 gene involved
in melanogenesis in the iris and retina; 1/60,000 males
Deficiency or lack of melanin pigment in skin, hair, and eyes
Risk of sunburn and **skin cancer**
Abnormal ocular development with poor visual acuity, nystagmus, lack of binocular
vision and **sensitivity to bright light**
Alkaptonuria - ANSWER-AR
Mutation in gene HGD, which encodes homogentisic acid oxidase
Urine that darkens over time after voiding
Deposition of homogentisic acid in connective tissue similarly leads to darkening
Arthritis, particularly of the spine, develops beginning in the 3rd decade
, Kidney dysfunction
Clinical trials testing nitisinone, which is an inhibitor of 4- hydroxylphenylpyruvate
dioxygenase, the enzyme that produces homogentisic acid
Alzheimer disease - ANSWER-Multifactorial; EOAD is AD with mutations in the genes
PSEN1 > APP > PSEN2
Encoding presenilin-1, amyloid beta A4 protein and presenilin-2, respectively
e4 allele at APOE locus is a risk factor
Upwards of 5% of individuals over 70 years of age have signs of AZD or dementia
Less than 2% of cases are due to single gene mutations
First-degree relatives face 20-25% risk of developing AZD
Androgen insensitivity syndrome - ANSWER-XLR
Some carriers will manifest due to nonrandom X chr inactivation
1/20,000 - 1/50,000
Mutation in AR gene, which encodes the androgen receptor
**Those with complete insensitivity have normal female external genitalia**
Undescended testes
Lack uterus and Fallopian tubes due to action of Mullerian-inhibiting substance
Those with partial insensitivity have some degree of masculinization of the external
genitalia, and may present with ambiguous genitalia
**Gonadectomy is performed after puberty to prevent gonadoblastoma**
Vaginal dilation
Sex assignment and management is a complex issue
Follow with surgical, endo, genetic and psych
Angelman syndrome - ANSWER-Genomic imprinting disorder
68% Deletion of the maternal 15q11.2-q13 region
11% **UBE3A** gene mutation (AD)
7% Paternal UPD of chr 15
3% Small imprinting region deletions (AD)
1/12,000 - 1/20,000
Severe DD, seizures, hyperactivity, abnormal gait
Recurrence is rare
Ataxia - ANSWER-Genetically heterogeneous; most forms AD
Friedreich ataxia is AR; FXN gene (frataxin)
**GAA triplet repeat expansion within an INTRON**
Normal alleles contain 5 - 33 repeats
Permutation alleles 33 - 65 repeats
Borderline alleles 44-66 repeats
Full penetrance disease alleles 66-1700 repeats
Hereditary ataxia syndromes may manifest as pure ataxia or ataxia in association with
other symptoms
Friedreich ataxia usually has **onset in late childhood or adolescence**, although later
onset may occur
