Alina T. Midro

Genotype–phenotype correlation in 21 patients with Wolf–Hirschhorn syndrome using high resolution array comparative genome hybridisation (CGH)

Background: The Wolf-Hirschhorn syndrome (WHS) is usually caused by terminal deletions of the short arm of chromosome 4 and is phenotypically defined by growth and mental retardation, seizures, and specific craniofacial manifestations. Large variation is observed in phenotypic expression of these features. In order to compare the phenotype with the genotype, we localised the breakpoints of the 4pter aberrations using a chromosome 4 specific tiling BAC/PAC array. Methods: In total, DNA from 21 patients was analysed, of which 8 had a cytogenetic visible and 13 a submicroscopic deletion. Results and conclusion: In addition to classical terminal deletions sized between 1.9 and 30 Mb, we observed the smallest terminal deletion (1.4 Mb) ever reported in a patient with mild WHS stigmata. In addition, we identified and mapped interstitial deletions in four patients. This study positions the genes causing microcephaly, intrauterine and postnatal growth retardation between 0.3 and 1.4 Mb and further refines the regions causing congenital heart disease, cleft lip and/or palate, oligodontia, and hypospadias.

Rett syndrome in females with CTS hot spot deletions: a disorder profile.

From a series of 107 females with Rett syndrome (RTT), we describe the long‐term history of ten females with a deletion in the C‐terminus of the MECP2 gene. We observed that their disorder profile is clinically recognizable with time and different from other atypical and milder RTT phenotypes. In females with hot spot deletions in the C‐terminus, dystonia is present from childhood and results in a serious spine deformation in spite of preventive measures. Their adaptive behavior is surprisingly better preserved and in contrast with the typical decline in motor functioning. The delineaton of disorder profiles by long‐term clinical observation can teach us about genotype/phenotype relationships and eventually about the effect of epigenetic phenomena on the final phenotype.

Second observation of Silver-Russel syndrome in a carrier of a reciprocal translocation with one breakpoint at site 17q25

Clin Genet 1993: 44: 53–55.

Experiences with risk estimates for carriers of chromosomal reciprocal translocations

Midro AT, Stengel‐Rutkowski S, Stene J. Experiences with risk estimates for carriers of chromosomal reciprocal translocations. Clin Genet 1992:41: 113–122.

Interstitial deletion 9q22.32-q33.2 associated with additional familial translocation t(9;17)(q34.11;p11.2) in a patient with Gorlin–Goltz syndrome and features of Nail-Patella syndrome

The phenotype of Gorlin–Goltz syndrome or basal cell nevus syndrome (BCNS, #109400, OMIM), a Mendelian trait due to PTCH mutations has been reported in a few cases of interstitial deletion of chromosome 9q. We present an 11‐year‐old girl with clinical features consistent with BCNS including bridging of sella turcica, biparietal bossing, downward slanting palpebral fissures, mandible prognathism, pectus excavatum, thumb abnormalities, occult spina bifida at L5‐S4, numerous basal cell nevi, and single basal cell carcinoma. Cytogenetic analysis using high‐resolution banding techniques and fluorescence in situ hybridization (FISH) revealed interstitial chromosome deletion 9q22.32‐q33.2 involving the PTCH gene as a secondary breakage event to a chromosome translocation t(9;17)(q34.1;p11.2)mat. Further FISH studies showed the translocation breakpoint on 9q34.11 maps proximal to ABL, between the BAC clone RP11‐88G17 and the LMX1B gene. The latter gene encodes a transcription factor, in which loss of function mutations are responsible for the nail‐patella syndrome (NPS, #161200 OMIM). Interestingly, some features of our proband (e.g., bilateral patellar dysplasia and abnormal clavicular shape), as well as her healthy sister who carries the same translocation, are also found in patients with NPS. The chromosome 17p11.2 breakpoint maps in the Smith‐Magenis syndrome common deletion region, within two overlapping BAC clones, CTD‐2354J3 and RP11‐311F12.

Genetic counseling in Robertsonian translocations der(13;14): Frequencies of reproductive outcomes and infertility in 101 pedigrees

Robertsonian translocations 13/14 are the most common chromosome rearrangements in humans. However, most studies aimed at determining risk figures are more than 20 years old. Their results are often contradictory regarding important topics in genetic counseling such as infertility and unfavorable pregnancy outcomes. Here, we present a study on a sample of 101 previously unreported pedigrees of der(13;14)(q10;q10). In order to minimize problems of partial ascertainment, we included families with a wide range of reasons of ascertainment such as birth of a child with congenital anomalies, prenatal diagnosis due to maternal age, fertility problems and recurrent pregnancy loss. No evidence of increased infertility rates of female and male carriers was found. The detected miscarriage frequency of female carriers was higher than previously reported (27.6 ± 4.0% of all spontaneous pregnancies). This may be explained by an over‐correction of earlier studies, which excluded all unkaryotyped miscarriages. In three out of 42 amniocenteses, translocation trisomies 13 were diagnosed (7.1 ± 4.0% of all amniocenteses). The frequency of stillbirths was 3.3 ± 1.6% for female carriers and 1.4 ± 1.4% for male carriers. A low risk for the live birth of translocation trisomy 13 children was confirmed since no live born children with trisomy 13 or Pätau syndrome were detected in the ascertainment‐corrected sample.

Risk evaluation of carriers with chromosome reciprocal translocation t(7;13)(q34;q13) and concomitant meiotic segregation analyzed by FISH on ejaculated spermatozoa

We performed the segregation analysis of a relatively large pedigree of t(7;13)(q34;q13) carriers together with the sperm karyotype analysis of the one carrier using a tri‐color fluorescence in situ hybridization (FISH) method. The risk assessments for unfavorable pregnancy outcomes in a series of 36 pregnancies in eight reciprocal chromosome translocation (RCT) couples of carriers were estimated directly from a pedigree after ascertainment correction. The individual probability rate for unbalanced child was predicted according to Stengel‐Rutkowski and co‐workers. The unbalanced karyotypes in the form of monosomy 7q34 → qter and trisomy 13q13 → qter were detected among stillborn/early death newborns with holoprosencephaly (HPE), cyclopia and other malformations. Based on clinical description of unkaryotyped stillbirth progeny, it can be assumed that the phenotype distinctions were connected with the unbalanced karyotype from 2:2 segregation (monosomy 7q with trisomy 13q) and 3:1 segregation as interchange trisomy 13 (Patau syndrome). Probability rates for miscarriages, stillbirth/early death were 12.9 ± 6% (4/31) and 29 ± 8.2% (9/31), respectively. The results of the meiotic segregation pattern indicated the rate of unbalanced spermatozoa for about 60%, with the unusual high rate (29.4%) of 3:1 segregant (i.e., 13.4% of the tertiary segregation and 16% of the interchange segregation). Adjacent‐1 segregation followed with 23.5% and adjacent‐2 followed with 7.2% of analyzed spermatozoa. The high rate of unbalanced gametes in comparison to the number of stillborn/early death and miscarriages detected in pedigree suggests a strong selection against unbalanced chromosomal constitutions during fetal development. It corresponds to a very small probability rate (about 0.3%) of viable unbalanced progeny from 3:1 meiotic segregation predicted for maternal carriers. This knowledge can be used in genetic counseling of families with similar RCT ascertained in a different way.

XYY syndrome and acute myeloblastic leukemia

A 69-year-old man with hypogonadism was found to have a 47,XYY karyotype. Clinical and laboratory data revealed acute nonlymphocytic leukemia (ANLL) of the M2 type. The association between the XYY and ANLL-M2 is most likely accidental coincidence.

L239F founder mutation in GDAP1 is associated with a mild Charcot-Marie-Tooth type 4C4 (CMT4C4) phenotype.

Over 40 mutations in the GDAP1 gene have been shown to segregate with Charcot–Marie–Tooth disease (CMT). Among these, only two mutations, i.e., S194X and Q163X have been reported in a sufficient number of CMT families to allow for the construction of reliable phenotype–genotype correlations. Both the S194X and Q163X mutations have been shown to segregate with an early-onset and severe neuropathy resulting in loss of ambulance at the beginning of the second decade of life. In this study, we identified the L239F mutation in the GDAP1 gene in one Bulgarian and five Polish families. We hypothesized that the L239F mutation may result from a founder effect in the European population since this mutation has previously been reported in Belgian, Czech, and Polish patients. In fact, we detected a common disease-associated haplotype within the 8q13-q21 region in the Polish, German, Italian, Czech, and Bulgarian CMT families. Like the previously detected “regional” S194X and Q163X mutations, respectively present in Maghreb countries and in patients of Spanish descent, the L239F mutation seems to be the most common GDAP1 pathogenic variant in the Central and Eastern European population. Given the likely presence of a common ancestor harboring the L239F mutation, we decided to compare the phenotypes of the CMT (L239F) patients collected in this study with those of previously reported cases. In contrast to CMT4A caused by the S194X and Q163X mutations, the CMT phenotype resulting from the L239F substitution represents a milder clinical entity with a long-preserved period of ambulance at least until the end of the second decade of life.

Wolf–Hirschhorn syndrome-associated chromosome changes are not mediated by olfactory receptor gene clusters nor by inversion polymorphism on 4p16

The basic genomic defect in Wolf–Hirschhorn syndrome (WHS), including isolated 4p deletions and various unbalanced de novo 4p;autosomal translocations and above all t(4p;8p), is heterogeneous. Olfactory receptor gene clusters (ORs) on 4p were demonstrated to mediate a group of WHS-associated t(4p;8p)dn translocations. The breakpoint of a 4-Mb isolated deletion was also recently reported to fall within the most distal OR. However, it is still unknown whether ORs mediate all 4p-autosomal translocations, or whether they are involved in the origin of isolated 4p deletions. Another unanswered question is whether a parental inversion polymorphism on 4p16 can act as predisposing factor in the origin of WHS-associated rearrangements. We investigated the involvement of the ORs in the origin of 73 WHS-associated rearrangements. No hotspots for rearrangements were detected. Breakpoints on 4p occurred within the proximal or the distal olfactory receptor gene cluster in 8 of 73 rearrangements (11%). These were five t(4p;8p) translocations, one t(4p;7p) translocation and two isolated terminal deletions. ORs were not involved in one additional t(4p;8p) translocation, in a total of nine different 4p;autosomal translocations and in the majority of isolated deletions. The presence of a parental inversion polymorphism on 4p was investigated in 30 families in which the 4p rearrangements, all de novo, were tested for parental origin (7 were maternal and 23 paternal). It was detected only in the mothers of 3 t(4p;8p) cases. We conclude that WHS-associated chromosome changes are not usually mediated by low copy repeats. The 4p16.3 inversion polymorphism is not a risk factor for their origin.