Week 6 2024 Sex Chr Abnormalities.pdf

SEX CHROMOSOME ABNORMALITIES TYPES OF ABNORMALITIES ⚫ ⚫ ⚫ ⚫ Structural – translocations, inversions, isochromosomes, deletions, duplications Numerical Mosaic Involving autosomes (1-22) Karyotyping notes: Constitutional aneuploidies are listed as the sex chromosome complement: A single X chromoso...

SEX CHROMOSOME ABNORMALITIES TYPES OF ABNORMALITIES ⚫ ⚫ ⚫ ⚫ Structural – translocations, inversions, isochromosomes, deletions, duplications Numerical Mosaic Involving autosomes (1-22) Karyotyping notes: Constitutional aneuploidies are listed as the sex chromosome complement: A single X chromosome is written as 45,X An additional X chromosome is written as 47,XXX Acquired aneuploidies in known normal constitutional karyotypes are indicated as losses or gains A single X chromosome in a female is written 45,X,-X An additional X chromosome in a female is written as 47,XX,+X X CHROMOSOME Genes encode house-keeping and specialised functions. It does not encode sex determination or differentiation. In females one of the X-chromosomes is inactivated in each and every cell. [Lyonisation - known since 1961] The process starts at the "X inactivation centre" ( XIC ) in Xq13 and spreads along the chromosome. XIC works by counting the X chromosomes, so only one X remains active per diploid set X-INACTIVATION The breakthrough was the discovery of the X inactive specific transcript: XIST (Brown et. al., (1991) Nature 349, 372-373.) This gene is located within the "XIC” and only expressed by the inactive X chromosome. XIST appears to initiate X inactivation and it is the methylation of the inactive X genes that renders them inactive. X chromosome-controlling element (XCE) affects the choice of X chromosome to be inactivated in any cell. Inactivation can be skewed but rarely more than 70:30 Pseudoautosomal regions (PAR) at the tips of X (PAR1 at Xp terminal and PAR2 at Xq terminal) remain genetically active on both X chromosomes in females and also on the X and Y in males. TURNER SYNDROME – 45,X (MONOSOMY X) Short stature due to loss of SHOX (short stature homeobox) gene at Xp ⚫ Swelling in hands and feet (disappearing after birth) ⚫ Webbed neck, broad chest with widely-spaced nipples ⚫ ⚫ ⚫ Infertile - failure to develop secondary sexual characteristics Normal IQ VARIANT TURNER SYNDROME 45,X/46,XX 45,X/47,XXX 45,X/46,i(Xq) 45,X/46,X,del(Xp) 45,X/46,X,del(Xq) 45,X/46,X,altered Y KLINEFELTER SYNDROME - 47,XXY Normal face Tall, tendency toward long arms and legs Small testes fail to produce normal levels of testosterone Gynaecomastia 40% Slightly lower IQ Infertility Rare 48,XXXY and 49,XXXXY severe retardation 47,XXY 48,XXXY KLINEFELTER SYNDROME - 47,XXY OTHER NUMERICAL ABNORMALITIES 47,XXX Mostly normal phenotype in most individuals with normal fertility (possibility of premature ovarian failure) IQ 82 (10-20 points lower than sibs), learning difficulties with language and speech impaired Motor skills also delayed 47,XYY Mostly normal phenotype in most individuals with normal fertility Tall IQ normal but usually lower than siblings, some minor learning difficulties and behavioural issues. X CHROMOSOME ALTERATIONS X DELETIONS Deletions of X more common than those of autosomes Can be transmitted from a 46,X,del(X) mother to “phenotypically normal” carrier daughter but would result in abnormal son ie 46,Y,del(X) Female with deletion in Xp may have short stature due to deletion of the SHOX gene (PAR1 region remains active) Female with deletion in Xq may experience premature ovarian failure (POF) Rarely a recessive X-linked disease may be exposed in female Males will be nullisomic for loci in the deleted region. Only a microdeletion in a male fetus may be viable, but the absence of loci leads to a contiguous gene syndrome – abnormal phenotype. X CHROMOSOME ALTERATIONS X DELETIONS CONTINUED Xp21 Duchenne muscular dystrophy (DMD), retinitis pigmentosa, adrenal hypoplasia, glycerol kinase deficiency and mental retardation Xp22.3 Steroid sulfatase gene (STS), causes X-linked ichthyosis Kallmann gene (ANOS1) leads to hypogonadism and anosmia CDPX gene causes skeletal dysplasia Ring X 45,X/46,X,r(X) Phenotype variable depending on the amount of chromosome lost and inactivation pattern – rarely seen in males Tiny ring X syndrome associated with severe MR due to functional X disomy, due to absence of XIST 46,X,del(X)(q13) X CHROMOSOME ALTERATIONS X Duplications Caused by direct duplication, inverted duplication or isochromosome 1:1 segregation expected in the female heterozygote Can be transmitted from a 46,X,dup(X) carrier mother to carrier daughter If the rule of selective Lyonisation holds, the abnormal X should be inactivated, phenotypic normality should be expected. Male with a duplicated X will have an abnormal phenotype ie 46,Y,dup(X) Xp21.1-21.2 duplication may lead to sex reversal, with ovarian formation and female or ambiguous genitalia, due to disomic expression of gene SRVX Long (q) arm duplications lead to very abnormal phenotype in males. In females phenotype less predictable. Micro-dulpication can occasionally lead to a Mendelian disorder 46,X,dup(X)(q12q28) X-AUTOSOME TRANSLOCATIONS FEMALES Balanced female X-autosome carrier, 46,X,t(X;autosome) Have two translocation chromosomes, the der(X) and the der(autosome) Usually the der(X) contains the XIC, the X segment on the der(autosome) lacks the XIC The only way to achieve a functional balance is for the normal X to be inactive Unbalanced female X-autosome carrier, 46,X,der(X),t(X;autosome) Needs to have der(X) inactivated Usually a preferential inactivation of the der(X) if it contains XIC Inactivation can spread along the autosomal segment on the der(X) although unpredictable Partial Turner syndrome FEMALES cont. X Critical regions at Xq13-q22 and Xq22-q27 breakpoints in these regions invariably affect ovarian function. Premature ovarian failure to primary amenorrhea Disruption of X loci may expose X-linked Mendelian disorders classic historical example of Duchene/Becker muscular dystrophy at Xp21 (DMD gene) Lissencephaly gene XLIS at Xq22.3 MALES Balanced male X-autosome carrier, 46,Y,t(X;autosome) Invariably infertile due to spermatogenic arrest disruption of the sex vesicle is the presumed mechanism Unbalanced male X-autosome carrier, 46,Y,der(X),t(X;autosome) Not viable due to X nullisomy and autosomal trisomy Y-AUTOSOME TRANSLOCATIONS Balanced male Y-autosome carrier, 46,X,t(Y;autosome) NOT Acrocentric Have two translocation chromosomes, the der(Y) and the der (autosome) Usually the breakpoint is at Yq11.2 or Yq12 Most normal phenotype with infertility Occasionally phenotypic abnormalities due to gene disruption Yq and Acrocentric p Translocation No loss or gain of euchromatin; the result is the Y heterochromatin transfers onto the p arm of the acrocentric 50% are t(Y;15) Breakpoint is usually Yq12 and acrocentric p11-p13 Males and Females can be carriers of the derivative acrocentric This can be easily detected by C-banding X-Y TRANSLOCATIONS Classical X-Y translocation The breakpoints are constant Xp22.3 and Yq11 Deletion of distal Xp causes defect, genes- SHOX, STS, ANOS1, MRX , OA1 Female usually fertile and of normal intelligence, maybe short Male infertile and will display more severe phenotype Cryptic Xp-Yp translocation 46,XX male or 45,X male The breakpoints are Xp22.3 and Yp11 in the short arm proximal to SRY gene Genetic consequence is loss of Xp and transfer of SRY gene onto the almost intact X Arises from abnormal X-Y pairing during paternal meiosis. Affected males are infertile CLASSICAL X-Y TRANSLOCATION 46,X,der(X)t(X;Y)(p22.3;q11) CRYPTIC X-Y TRANSLOCATION 46,X,der(X)t(X;Y)(p22.3;p11) Cryptic X-Y translocation 46,X,der(X)t(X;Y)(p22.3;p11) FISH for X centromere (green) and SRY (red) Y CHROMOSOME ALTERATIONS Several possibilities deletions of Yp or Yq isochromosomes of Yp or Yq Ring Y 45,X mosaicism usually seen as well Loss of SRY on Yp11.3 leads to female development Loss of other Yp loci leads to Turner syndrome phenotype Intact Yp with loss of Yq loci particularly AZF loci is associated with infertility AZF regions, a,b,c & d. AZFc at Yq11.23 contains DAZ gene ( deleted in azoospermia) AZFa and AZFb deletions are more severe in effect AZF/DAZ accounts for 10-20% of male infertility AZFa 5%, AZFb 10%, AZFbc 13%, AZFc 70% and AZFabc 2% 46,X,i(Yp) Cband 46,X,i(Yp) 46,X,i(Y)(p10) FISH SRY(red) X centromere ( green) 46,XYqs 46,XYqs NOR staining 46,X,inv(Y): pericentric Y inversion Become a “metacentric” shaped chromosome Can be considered to be a likely normal variant. Does not normally interfere with fertility C-band G-band 45,X/46,X,r(Y) FISH X centromere Y centromere 18 centromere