Mary C. Phelan

Autism and maternally derived aberrations of chromosome 15q

Of the chronic mental disabilities of childhood, autism is causally least well understood. The former view that autism was rooted in exposure to humorless and perfectionistic parenting has given way to the notion that genetic influences are dominant underlying factors. Still, identification of specific heritable factors has been slow with causes identified in only a few cases in unselected series. A broad search for genetic and environmental influences that cause or predispose to autism is the major thrust of the South Carolina Autism Project. Among the first 100 cases enrolled in the project, abnormalities of chromosome 15 have emerged as the single most common cause. The four abnormalities identified include deletions and duplications of proximal 15q. Other chromosome aberrations seen in single cases include a balanced 13;16 translocation, a pericentric inversion 12, a deletion of 20p, and a ring 7. Candidate genes involved in the 15q region affected by duplication and deletion include the ubiquitin-protein ligase (UBE3A) gene responsible for Angelman syndrome and genes for three GABA(A) receptor subunits. In all cases, the deletions or duplications occurred on the chromosome inherited from the mother.

22q13 deletion syndrome

We have recently collected clinical information on 37 individuals with deletion of 22q13 and compared the features of these individuals with 24 previously reported cases. The features most frequently associated with this deletion are global developmental delay, generalized hypotonia, absent or severely delayed speech, and normal to advanced growth. Minor anomalies include dolicocephaly, abnormal ears, ptosis, dysplastic toenails, and relatively large hands. As with many terminal deletions involving pale G-band regions, the deletion can be extremely subtle and can go undetected on routine cytogenetic analysis. In fact, 32% of the individuals in our study had previous chromosome analyses that failed to detect the deletion. Eight of 37 individuals had deletion of 22q13 secondary to an unbalanced chromosome translocation. In the newborn, this deletion should be considered in cases of hypotonia for which other common causes have been excluded. In the older child, this syndrome should be suspected in individuals with normal growth, profound developmental delay, absent or delayed speech, and minor dysmorphic features. We recommend high-resolution chromosome analysis and fluorescence in situ hybridization studies, or molecular analysis to exclude this diagnosis.

22q13 Deletion Syndrome: An Update and Review for the Primary Pediatrician

Recent advances in genetic testing can help to provide a specific diagnosis to children born with syndromes that result in congenital anomalies and developmental delay. One such emerging condition is the 22q13 deletion syndrome. With the introduction of subtelomeric fluorescence-in-situ hybridization (FISH) analysis, the 22q13 deletion has become recognized as a relatively widespread and underdiagnosed cause of mental retardation. Primary-care physicians play an important role in the care of children with 22q13 deletion syndrome, from suspecting the diagnosis in a developmentally delayed child through the medical, developmental, and behavioral aspects of their care. Furthermore, they serve as a valuable source of support and advocacy for the family and a resource for other care providers. The remainder of this article addresses the current state of knowledge regarding 22q13 deletion syndrome and offers the primary-care physician a framework in which to provide care and information.

Two sisters with a distal deletion at the Xq26/Xq27 interface: DNA studies indicate that the gene locus for factor IX is present

SummaryTwo sisters with premature menopause and a small deletion of the long arm of one of their X chromosomes [del (X)(pter→q26.3:)] were investigated with polymorphic DNA probes near the breakpoint. The deleted chromosome retained the factor IX (F9) locus and the loci DXS51 (52A) and DXS100 (pX45h), which are proximal to F9. However, the factor VIII (F8) locus was not present, nor were two loci tightly linked to this locus, DXS52 (St14) and DXS15 (DX13) This deletion refines the location of the F9 locus to Xq26 or to the interface Xq26/Xq27, thus placing it more proximally than has been previously reported. The DNA obtained from these patients should be valuable in the mapping of future probes derived from this region of the X chromosome.

Split foot and developmental retardation associated with a deletion of three microsatellite markers in 7q21.2-q22.1

A deletion of 7q21.2‐q22.1 has been found in a patient with split foot and developmental retardation. Molecular analysis using polymerase chain reaction (PCR) showed deletion of three microsatellite markers, D7S527, D7S479 and D7S554, in the patients paternal chromosome. These results pinpoint the critical region for an ectrodactyly locus (SHFD1) on chromosome 7.

Two patients with duplication of 17p11.2: The reciprocal of the Smith-Magenis syndrome deletion?

J.M. and H.G. are two unrelated male patients with developmental delay. Cytogenetic analysis detected a duplication of 17p11.2 in both patients. The extent of the duplicated region was determined using single copy DNA probes: cen-D17S58-D17S29-D17S258-D17S71-D17S445-+ ++D17S122-tel. Four of the six markers, D17S29, D17S258, D17S71, and D17S445, were duplicated by dosage analysis. Fluorescent in situ hybridization (FISH) analysis of H.G., using cosmids for locus D17S29, confirmed the duplication in 17p11.2. Because the deletion that causes the Smith-Magnesis syndrome involves the same region of 17p11.2 as the duplication in these patients, the mechanism may be similar to that proposed for the reciprocal deletion/duplication event observed in Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and Charcot-Marie-Tooth Type 1A disease (CMT1A).

DNA methylation analysis with respect to prenatal diagnosis of the Angelman and Prader–Willi syndromes and imprinting

The Angelman (AS) and Prader–Willi syndromes (PWS) are clinically distinct neurobehavioural syndromes resulting from loss of maternal (AS) or paternal contributions (PWS) of imprinted genes within the chromosomal 15q11‐q13 region. The molecular diagnosis of both syndromes can be made by a variety of techniques, including DNA methylation, DNA polymorphism and molecular cytogenetic analyses. DNA methylation analysis at three major loci (ZNF127, PW71 and 5′ SNRPN) has been successfully used for the postnatal diagnosis of AS and PWS. Methylation analysis, in contrast to other techniques, can reliably be used to diagnose all three major molecular classes (deletion, uniparental disomy and imprinting mutation) of PWS, and three of the four major classes of AS. In this study we demonstrate that methylation analysis can also be successfully used in prenatal diagnosis, by examining specimens obtained from amniocentesis and chorionic villus sampling. Correct prenatal diagnoses were obtained in 24 out of 24 samples using the 5′ SNRPN locus; 4 out of 15 using the ZNF127 locus; and 10 out of 18 using the PW71 locus. Therefore, our data indicate that although the DNA methylation imprints of ZNF127 and 5′ SNRPN arise in the germline and are present in brain, only 5′ SNRPN maintains the imprint in tissues suitable for the prenatal diagnosis of AS and PWS. Copyright

FISH analysis of a complex chromosome rearrangement involving nine breakpoints on chromosomes 6, 12, 14 and 16

We report the prenatal diagnosis of an apparently balanced de novo complex chromosome rearrangement (CCR) which involved nine breakpoints on four different chromosomes. Fluorescence in situ hybridization (FISH) and spectral karyotyping (SKY) were performed as an adjunct to G‐banding for characterization of the abnormal chromosomes. The 22‐week female fetus showed minor dysmorphic features including dolichocephaly, broad fingernails, tibial bowing, clubfoot, thoracolumbar scoliosis and hypoplastic toenails. Autopsy revealed gall‐bladder hypoplasia and an atrial septal defect. Chromosome analysis of fetal tissue confirmed the presence of the complex rearrangement. Copyright

Intersitial deletion of 20p: New candidate region for Hirschsprung disease and autism?

We describe a patient with Hirschsprung disease and autism. High-resolution karyotyping indicated that the patient has an interstitial deletion of 20p11.22-p11.23. Microsatellite analysis showed a deletion involving a 5-6 cM region from the maternally derived chromosome 20. The deleted region is proximal to, and does not overlap, the recently characterized Alagille syndrome region. This region of 20p has not yet been implicated in Hirschsprung disease or autism. However, this region contains several genes that could plausibly contribute to any phenotype that includes abnormal neural development.

Vascular anastomoses leading to amelia and cutis aplasia in a dizygotic twin pregnancy

Dichorionic placentation is observed in both monozygotic (MZ) and dizygotic (DZ) twinning, while monochorionic placentation is unique to MZ twinning. Examinations of monochorionic twin placentas frequently reveal the presence of vascular anastomoses between the two fetal circulations; such anastomoses rarely occur in dichorionic placentas. Consequently, abnormalities resulting from placental vascular communications are almost exclusively observed in MZ twin pairs with monochorionic placentas. We report opposite‐sex DZ twins in which vascular anastomoses occurred within a fused dichorionic placenta and were associated with vascular disruptions in one twin. The liveborn male twin had amelia, cutis aplasia, and XX/XY blood chimerism; the female twin died in utero.