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Single most common genetic cause of moderate mental retardation
Down Syndrome
Features of Down S.
  • characteristic dysmorphic facial features
  • short stature
  • brachycephaly with flat ociput
  • short neck
  • flat nasal bridge
  • brushfield spots around margin of iris
  • open mouth
  • Furrowed protruding tongue
  • epicanthal folds & upslanting palpebral fissures
  • dermatoglyphics
  • wide gap between 1st & 2nd toes
  • Simian crease
How is diagnosis of Down S. made?
Clinical diagnosis
2 reasons for karyotyping Down S.
  • Confirm clinical diagnosis
  • Karyotype essential for determining recurrence risk for parents.
Various karyotypes of Down S.and associated %

  • 95%: 47,XX or XY,+21

  • 4%: 46,XX or XY,rob(14;21)(q10;q10),+21 or der(14;21)

  • 2%: mosaic

Recurrence risk of 21q21q translocation in Down S.
Very low, because thought to originate as isochromosome (rather than Robertsonian translocation) that arises postzygotically
Incidence of Down S. in live births
% of Down S. babies born to mothers less than 35 years
Greater than 50% because they give birth so much more frequently.
Are mothers with one Down S. child at increased risk compared to general population for recurrence in subsequent children (assuming no translocation)?
  • Yes, 1.4% for mothers younger than 30
  • No, for older mothers (same age-adjusted risk as general population)
Trisomy 18 phenotype
  • Prominent occiput
  • Receding jaw
  • Clenched fists (overlapping 2nd & 5th fingers)
  • Rocker-bottom feet
  • 60% Female
Karyotype trisomy 18
Many (like Down Syndrome)
  • 20% have translocation
Incidence trisomy 18 in live births
1:8000 (actually 1:7500, but I am remembering 1:800, 1:8000, 1:16,000 for +21,+18, and +13, respectively)
Phenotype trisomy 13
  • Multiple midline defects
  • Severe CNS malformations (arhinecephaly, holoprosencephaly)
  • Cleft lip & palate
  • Microcephaly & wide open sutures
  • Ocular abnormalities: Micropthalmia, iris coloboma, or absent eyes
  • Malformed ears
  • Axial polydactaly
  • Clenched fists
  • Think of as "most unlucky, and rarest)
Incidence trisomy 13 in live birth
1:16,000 (Range 1:15,000-25,000)
Definition "autosomal deletion syndrome" & give most common syndrome
  • Cytogenetically detectable deletion
  • Cri du Chat
Chromosome involved in Cri du Chat
Phenotype Cri du Chat
  • Cat-like cry
  • Moderate-severe MR
  • Characteristic face (hypertelorism, epicanthus, retrognathia)
  • Heart defects
Definition microdeletion & duplication syndromes
Small but sometimes cytogenetically visible (usually requires, high-resolution karyotyping, FISH, or CGH) genetic imbalance referred to as segmental aneusomy or contiguous gene syndrome because phenotype attributable to haploinsufficiency for multiple contiguous genes within deleted region (vs. single gene)
Cause of deletion/duplications in contiguous gene syndromes
  • Aberrant recombination in low-copy repeated sequences.
  • AKA: Genomic disorders involving recombination between low-copy repeat sequences.
Genomic disorders involving 17p (4)
  • Smith-Magenis: del(17)(p11.2)
  • dup(17)(p11.2p11.2) syndrome (mild neurobehavioral phenotype)
  • Charcot-Marie-Tooth: duplication 17p12
  • HNLPP (hereditary neuropathy with liability to pressure palsies) deletion 17p12
Phenotype Smith-Magenis S.
Genomic disorders involving 22q (3)
  • DiGeorge S/ velocardiofacial syndrome/ conotruncal anomaly face S.: deletion 22q11.2
  • 22q11.2 duplication syndrome (dysmorphic malformations and birth defects)
  • Cat-eye S. (ocular coloboma, congenetial heart defects, craniofacial anomalies and MR): tetrosomy for 22q11.2
Phenotype DiGeorge S.
  • Craniofacial anomalies
  • Immune deficiency (hypoplastic thymus)
  • MR
  • Heart defects (particulary tetrology of fallot and pulmonary atresia/absent pulmonary valve)
  • Hypocalcemia (abnormal parathyroids)
Gene implicated in DiGeorge S. phenotype
TBX1 encodes transcription factor involved in development of pharyngeal system
List chromosomal abnormality of following genomic disorders involving recombination between low-copy repeat sequences:
  • Smith-Magenis
  • Charcot-Marie-Tooth (CMT1A)
  • DiGeorge
  • Cat-eye S.
  • Prader-Willi/Angelman
  • Williams S.
  • Neurofibromatosis I
  • Sotos S.
  • Azoospermia (AZFc)
  • Smith-Magenis S.: del 17p11.2
  • Charcot-Marie-Tooth (CMT1A): dup 17p12
  • DiGeorge: del 22q11.2
  • Cat-eye S.: tetrosomy 22q11.2
  • Prader-Willi/Angelman: del 15q11-q13
  • Williams S.: del 7q11.23
  • Neurofibromatosis I: del 17q11.2
  • Sotos S.: del 5q35
  • Azoospermia (AZFc): del Yq11.2
Do X & Y undergo recombination?
Yes, in pseuoautosomal regions (ends of long and short arms)
Genetic attributes of Y chromosome
  • Gene poor (50 genes)
  • Most genes involved in gonadal and genital development
Critical gene involved in testicular development
SRY/TDF expressed briefly early in development just before testicular development
Abnormality in XX male
Usually Y translocation to X
Abnormality in XY female
Loss of SRY (some cases)
Important genes in spermatogenesis
  • AZF genes (azoospermia factors) on Y chromosome
  • USP9Y (De novo point mutation implicated in male infertility)
Mechanism of gene inactivation on inactive X chromosome
DNA methylation of cytosine by DNA methyltransferase (restricted to CpG dinucleotides)
Are all X genes on the inactivated X inactive?
No, as many as 50% on distal Xp escape inactivation, consequently, imbalances involving this region may have greater clinical significance than imbalance of Xq
X Inactivation center and XIST gene
Proximal Xq contains XIST (X inactivator specific transferases) expressed only from allele on inactive X, which codes for noncoding RNA which associates with inactive X (barr body), which is necessary for X inactivation.
Is X inactivation random
X inactivation is random unless there is structurally abnormal X
Situations in which X inactivation is not random
  • X;autosome translocation (balanced): Normal X inactivated to preserve balance
  • X;autosome translocation (unbalanced): abnormal X invariably carries inactivation center, which is inactivated. Normal X is active
Explanation for female patient that manifests X-linked phenotype normally seen only in males
Balanced translocation in which normal X is preferentially inactivated and only abnormal X is active.
MR associated with X chromosome
High frequency of mutations, microdeletions or duplications that cause X-linked mental retardation (20-40% excess of MR males in large scale population studies)
As a group, are there any predisposing factors in sex chromosome disorders?
No, except for late maternal age in cases originating from maternal meiosis I.
Indications for cytogenetic or molecular study for sex chromosome disorder
  • Delayed puberty
  • primary or secondary amenorrhea
  • Infertility
  • Ambiguous genitalia
Incidence of sex chromosome abnormalities in live births
  • Very common, 1:400
Most common type of sex chromosome defects?
NUMERICAL (Very common)
  • Liveborn: trisomies (XXY, XXX, XYY)
  • Stillborn: Turner (X,O)
  • isochromosomeof long arm of X, i(Xq), seen in at least 15% of Turner S. (complete or mosaic)
In general, are autosomal or sex chromosomal abnormalities more severe?
Autosomal abnormalities generally much more severe. Most sex chromosomal abnormalities only have mild developmental abnormalities.
4 well-defined syndromes associated with sex chromosome aneuploidy
  • Klinefelter s. (47,XXY)
  • 47, XYY S.
  • Trisomy X (47,XXX)
  • Monosomy X (45, X)
  • Phenotype?
  • Karyotype?
  • Cause?
  • Phenotype: tall, hypogonadism (infertility), gynocomastia (increased risk breast cancer), persistent androgen deficiency
  • Karyotypes: 47,XXY, 48XXYY, 49XXXXY (MR increases with Xs)
  • Cause: 50% errors in paternal meiosis I due to failure on normal Xp/Yp recombination
47,XYY Syndrome

  • Phenotype?

  • Cause?

47,XXY Syndrome

  • Phenotype: tall, frequent behavioral problems

  • Cause: paternal non-dysjunction at meiosis II producing YY sperm

Trisomy X
  • Phenotype?
  • Karyotype?
  • Cause?
Trisomy X
  • Phenotype: tall, learning difficulties
  • Karyotype: 47XXX (also tetrasomy X & pentasomy X, which increase in severity like in Klinefelters)
  • Cause: maternal non-dysjunction at meiosis I

Turner Syndrome Phenotype
  • short stature
  • webbed neck (cystic hygroma/lymphadema)
  • low posterior hairline
  • broad chest with wide-spaced nipples
  • renal & cardiovascular abnormalities
  • coarctation aorta
  • Edema of hands & feet
  • streak gonads (gonadal dysgenesis)
  • slightly decreased IQ & learning difficulty (particularly in math)
incidence of all sex-chromosome triploidies
approximately 1:1000
definition hemaphroditism
Both ovarian and testicular tissue present
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