Prenatal diagnosis of trisomy 18p and distal 21q22.3 deletion

OBJECTIVES: To present the perinatal findings and molecular cytogenetic analysis of concomitant trisomy 18p (18p11.2-->pter) and distal 21q22.3 deletion. CASE AND METHODS: A 29-year-old woman, gravida 2 para 1, underwent amniocentesis at 17 weeks' gestation because she was a carrier of a balanced reciprocal translocation, 46,XX,t(18;21)(p11.2;q22.3). Cytogenetic analysis of the cultured amniocytes revealed a karyotype of 46,XX,der(21)t(18;21)(p11.2;q22.3). The fetus had a derivative chromosome 21 with an extra short arm of chromosome 18 attached to the terminal region of the long arm of chromosome 21. Level II sonograms did not find prominent structural anomalies. The pregnancy was terminated subsequently. At autopsy, the proband displayed a mild phenotype of hypertelorism, a small mouth, micrognathia, a narrowly arched palate, low-set ears, and clinodactyly. The brain and other organs were unremarkable. Genetic marker analysis showed a distal deletion at 21q22.3 and a breakpoint between D21S53 (present) and D21S212 (absent), centromeric to the known holoprosencephaly (HPE) minimal critical region D21S113-21qter. CONCLUSION: Genetic marker analysis helps in delineating the region of deletion in prenatally detected unbalanced cryptic translocation. Fetuses with concomitant trisomy 18p and distal 21q22.3 deletion may manifest inapparent phenotypic abnormalities in utero. Haploinsufficiency of the HPE critical region at 21q22.3 may not cause an HPE phenotype.     

A paternally inherited terminal deletion, del(8)(p23.1)pat, detected prenatally in an amniotic fluid sample: a review of deletion 8p23.1 cases.

A subtle terminal deletion of the short arm of chromosome 8 with a breakpoint in p23.1 was detected in amniocytes. Parental chromosome studies revealed a similar deletion in the father. The fetus did not have any abnormalities in a level II ultrasound. The pregnancy was continued and resulted in the birth of a baby girl. The child was normal at six months of age and no heart murmur was detected. In a retrospective review of cases in our laboratory, four other cases with a deletion del(8)(p23.1) were found. Three were paediatric cases with microcephaly, developmental delay, ASD, VSD, pulmonic stenosis, congenital and behavioural abnormalities. One was a 29-year-old woman with a mosaic karyotype. She had a history of spontaneous abortions and no known cardiac defect. Using conventional cytogenetics and/or FISH studies with 8p telomere probe and 8 painting probe, the 8p23.1 deletions were shown to be either terminal or interstitial. The karyotype from the prenatal case was compared with the other cases of 8p23.1 deletions in our laboratory to see if there was a discernible difference in the size of the deletion. The deletion in the proband seemed to involve a more distal 8p23.1 breakpoint. In the father's high resolution chromosomes (550-850 band level) the breakpoint appeared to be 8p23.1 approximately 23.2 and FISH studies using an 8p telomeric probe confirmed a terminal deletion. Interstitial deletion of sub-band 8p23.1 was associated with phenotypic abnormalities and distal 8p23.2pter deletion was found in apparently normal individuals, therefore, 8p23.1 appears to be the critical region for clinical abnormalities.     

Recombination of a maternal pericentric inversion results in 22q13 deletion syndrome

We describe a 10-month-old boy with 22q13 deletion syndrome. Chromosomal analysis showed a partial duplication of 22p11.2-pter and a terminal deletion of 22q13.31-qter. Maternal chromosomal analysis showed a pericentric inversion of chromosome 22, with breakpoints at p11.2 and q13.31 [inv(22)(p11.2q13.31)]. The deleted chromosome resulted from a recombinant chromosome inherited from his mother. This is a rare case of 22q13 deletion syndrome associated with parental pericentric inversion of chromosome 22.     

Molecular and cytogenetic investigation of Y chromosome deletions over three generations facilitated by intracytoplasmic sperm injection

BACKGROUND: The azoospermic factor (AZF) region is critical for normal spermatogenesis since microdeletions and partial deletions have been associated with infertility. We investigate the diagnostic ability of karyotyping in detecting clinically relevant Y chromosome deletions. The clinical significance of heterochromatin deletions, microdeletions and partial AZFc deletions is also evaluated. METHODS: A patient with a Yq deletion, affected by severe oligoasthenoteratozoospermia, underwent intracytoplasmic sperm injection (ICSI) which resulted in the birth of a healthy baby boy. The patient, his father and his son underwent Y chromosome microdeletion and partial AZFc deletion screening. We also studied the aneuploidy rate in the sperm of the patient by fluorescent in situ hybridization. RESULTS: AZF microdeletions were absent in the family. However, microdeletion analysis confirmed that the Yq deletion was limited to the heterochromatin. We found a partial AZFc gr/gr deletion in all three family members. We observed an increased rate of sex chromosome aneuploidy in the infertile patient. CONCLUSIONS: Cytogenetic analysis was misleading in identifying the Yq breakpoint. Infertility observed in the patient was associated with the gr/gr partial deletion. However, because of the incomplete penetrance of gr/gr deletions, the consequence of the vertical transmission of the deletion through ICSI remains unknown.     

Prenatal diagnosis of holoprosencephaly (HPE) in a fetus with a recombinant (18)dup(18q)inv(18)(p11.31q11.2)mat

Alobar holoprosencephaly (HPE) was identified by ultrasonography at 18 weeks' gestation in a fetus of a 29-year-old G2P0A1 woman. HPE has been described in association with various chromosomal anomalies. Amniocentesis was performed and a rearrangement of chromosome 18 resembling an isochromosome for the long arm of chromosome 18 was found. Subsequently, the mother was found to have a pericentric inversion of chromosome 18 with breakpoints at p11.31 and q11.2. The karyotype of the fetus was re-interpreted as 46,XX, rec(18)dup(18q)inv(18)(p11.31q11.2)mat. This is the first case of a parental inversion leading to a deficiency of 18p11.31 to 18pter associated with HPE.     

Molecular diagnosis of a novel heterozygous 268C-->T (R90C) mutation in TGIF gene in a fetus with holoprosencephaly and premaxillary agenesis.

We report the sonographic diagnosis and molecular analysis of holoprosencephaly (HPE) and premaxillary agenesis in a second-trimester fetus with a 46,XY karyotype. Mutational sequence analyses for the entire coding region and exon-intron boundaries of SHH, ZIC2, SIX3 and TGIF genes identified a novel heterozygous missense TGIF mutation 268C-->T (CGC-->TGC change) that predicts an Arg90Cys substitution in the homeodomain region of TGIF. The proband's parents did not carry the mutation. The present case is an example of the heterogeneous entity of the HPE spectrum and demonstrates that adjunctive molecular analyses of distinct human genes for HPE can reassure genetic counselling by elucidating the genetic pathogenesis, especially in cytogenetically normal fetuses affected with HPE.     

A novel heterozygous missense mutation 377T > C (V126A) of TGIF gene in a family segregated with holoprosencephaly and moyamoya disease

OBJECTIVES: To identify whether any mutations of candidate genes including SHH, ZIC2, SIX3, and TGIF exist in a Taiwanese family segregated with holoprosencephaly (HPE) and moyamoya disease. METHODS: Genotypes of the candidate genes SHH, ZIC2, SIX3, and TGIF were determined in the family members who were available for analysis by sequencing. In addition, genomic regions of another 50 unrelated Taiwanese (100 chromosomes) were studied to verify whether the nucleotide changes we found were mutations or polymorphisms. RESULTS: A novel missense mutation 377T > C and two polymorphisms (420A > G and 487C > T) in the TGIF gene were identified. No mutations in SHH, ZIC2 and SIX3 were found. The mother of the three HPE fetuses was found to be afflicted with moyamoya disease. A brief review of the mutations as well as polymorphisms reported in the TGIF gene up to 2005 is given. CONCLUSION: Molecular diagnosis can help genetic counseling in HPE, which is a heterogeneous disorder with its phenotypic and genotypic spectrum highly widened and variable. The possible association between TGIF mutation and moyamoya disease noted in our study also appeared to be novel.     

Inherited interstitial deletion of chromosomes 5p and 16q without apparent phenotypic effect: further confirmation

We describe two families in which an inherited interstitial deletion is present without apparent associated phenotypic abnormalities. The first deletion was discovered in a 19-year-old male with a previously diagnosed peroxisomal disorder. High-resolution chromosome analysis was interpreted as 46,XY,del(5)(p14.1p14.3). The patient's phenotypically normal mother had the same interstitial deletion. Chromosome 5p14 deletion has been reported in a three-generation family without phenotypic anomalies. We hypothesize that the affected son's phenotype may be coincidental or represent unmasking of an autosomal recessive peroxisomal disorder in the deleted region. The second interstitial deletion was detected by amniocentesis for advanced maternal age. High-resolution chromosome analysis was interpreted as 46,XX,del(16)(q13q22). The same deletion was found in the healthy mother and a normal brother. The pregnancy was carried to term and resulted in the birth of a normal girl. We report these cases as further evidence that rare, unbalanced deletion of specific chromosomal regions may result in no phenotypic effect. Consequences may result from expression of an autosomal recessive disorder on the homologous chromosome. Identification of such deletions is especially important for prenatal diagnosis and genetic counselling.     

Prenatal findings and molecular cytogenetic analyses of partial trisomy 12q (12q24.32-->qter) and partial monosomy 21q (21q22.2-->qter)

OBJECTIVES: To present the prenatal findings and molecular cytogenetic analyses of partial trisomy 12q and partial monosomy 21q, and a review of the literature. METHODS: Amniocentesis was performed at 23 gestational weeks in a 33-year-old woman because of abnormal sonographic findings. Amniocentesis revealed a derivative chromosome 21, or der(21), with a deletion on the region of 21q22.2 and an addendum of a small chromosomal segment of unknown origin. The maternal karyotype was subsequently found to be 46,XX,t(12;21)(q24.32;q22.2). Level II ultrasound showed microcephaly, micrognathia, a ventricular septal defect, and rocker-bottom feet. The pregnancy was terminated. A malformed infant was delivered without the phenotype of holoprosencephaly (HPE). Fluorescence in situ hybridization (FISH) and polymorphic DNA markers were used to investigate the involved chromosomal segments. RESULTS: FISH study showed the absence of the signal of 21q subtelomeric probe and the presence of the signal of 12q subtelomeric probe in the der(21).The fetal karyotype was 46,XY,der(21) t(12;21)(q24.32;q22.2)mat. Genetic marker analysis showed a deletion at 21q22.2 and a breakpoint between D21S156 (present) and D21S1245 (absent). The deleted segment was measured about 4.5 Mb encompassing the HPE critical region. CONCLUSIONS: Molecular genetic analyses help in determining the prenatally detected unbalanced cryptic translocation as well as parental balanced subtle translocation. A duplication of 12q24.32-->qter and a deletion of 21q22.2-->qter may be associated with prenatal sonographic findings of microcephaly, borderline ventriculomegaly and cerebellar hypoplasia, micrognathia, a ventricular septal defect, and rocker-bottom feet. Haploinsufficiency of the HPE critical region at 21q22.3 may not cause an HPE phenotype.     

Prenatal diagnosis of partial monosomy 18p(18p11.2-->pter) and trisomy 21q(21q22.3-->qter) with alobar holoprosencephaly and premaxillary agenesis

A prenatal diagnosis of partial monosomy 18p(18p11.2-->pter) and trisomy 21q(21q22.3-->qter) in a fetus with alobar holoprosencephaly (HPE) and premaxillary agenesis (PMA) but without the classical Down syndrome phenotype is reported. A 27-year-old primigravida woman was referred for genetic counselling at 21 weeks' gestation due to sonographic findings of craniofacial abnormalities. Level II ultrasonograms manifested alobar HPE and median orofacial cleft. Cytogenetic analysis and fluorescence in situ hybridization (FISH) on cells obtained from amniocentesis revealed partial monosomy 18p and a cryptic duplication of 21q,46,XY,der(18)t(18;21)(p11.2;q22.3), resulting from a maternal t(18;21) reciprocal translocation. The breakpoints were ascertained by molecular genetic analysis. The pregnancy was terminated. Autopsy showed alobar HPE with PMA, pituitary dysplasia, clinodactyly and classical 18p deletion phenotype but without the presence of major typical phenotypic features of Down syndrome. The phenotype of this antenatally diagnosed case is compared with those observed in six previously reported cases with monosomy 18p due to 18;21 translocation. The present study is the first report of concomitant deletion of HPE critical region of chromosome 18p11.3 and cryptic duplication of a small segment of distal chromosome 21q22.3 outside Down syndrome critical region. The present study shows that cytogenetic analyses are important in detecting chromosomal aberrations in pregnancies with prenatally detected craniofacial abnormalities, and adjunctive molecular investigations are useful in elucidating the genetic pathogenesis of dysmorphism.     

A 13-year-old girl with 18p deletion syndrome presenting Turner syndrome-like clinical features of short stature,short webbed neck,low posterior hair line,puffy eyelids and increased carrying angle of the elbows

Objective

We report a 13-year-old girl with 18p deletion syndrome presenting Turner syndrome-like clinical features.

5p15缺失综合征合并4q32重复1例临床分析与基因诊断

目的 探讨5p15缺失综合征合并4q32重复的临床特征及分子遗传学特点.方法 回顾分析1例5p15缺失综合征合并4q32重复患儿的临床资料以及分子遗传学分析资料.结果 10月龄女性患儿,具有特殊面容、发育迟缓、先天性心脏病及喉软骨发育不良等临床表现.全外显子测序和染色体组拷贝数分析精确定位拷贝数异常改变的染色体片段区域...     

A de novo subtelomeric monosomy 11q (11q24.2-qter) and trisomy 20q (20q13.3-qter) in a girl with findings compatible with Jacobsen syndrome: case report and review

We report on a 2-year-old dysmorphic girl with prenatal and postnatal growth deficiency, cardiopathy, left-sided hydronephrosis due to pyelourethral junction stenosis, frequent respiratory infections and psychomotor retardation, in whom a de novo unbalanced submicroscopic translocation (11q;20q) was detected by subtelomeric multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analyses. Additional fluorescence in situ hybridization studies with locus-specific BAC probes and analyses with microsatellite markers revealed that this translocation resulted in a paternal chromosome 11q terminal deletion of approximately 8.9 Mb and a subtelomeric 20q duplication of approximately 3.7 Mb. A subtelomeric 20q trisomy has only been reported in four cases so far. A subtelomeric 11q deletion has been clinically reported in 18 patients. We review the clinical phenotype of these patients. We suggest that patients with a subterminal (11q24.2/25-qter) deletion may present with features of the well-known phenotype of terminal 11q deletion or Jacobsen syndrome.     

Jacobsen 综合征2例诊断及染色体缺失区域的定位分析

摘要：目的　诊断并精细定位2例Jacobsen 综合征（JBS）染色体缺失区域,探讨JBS基因型与表型的关系。方法　2006年12月至2009年7月北京大学第一医院儿科神经门诊以及北京市儿童医院神经内科门诊就诊的中重度脑发育迟缓/智力低下（developmental delay/mental retardation,DD/MR）患儿451例,采集患儿及其父母外周血,提取基因组DNA,通过多重连接依赖性探针扩增技术（multiplex ligation-dependent probe amplification,MLPA）对亚端粒区拷贝数进行筛查,并用2种SALSA MLPA试剂盒（P070和P036）进行相互验证,阳性结果者进一步对其父母标本进行检测了解是否为新发;对MLPA检测阳性的新发拷贝数异常者行Affymetrix SNP6.0芯片检测以进一步验证,并精确定位明确拷贝数异常的片段范围。结果　451例患儿中发现2例存在11q远端缺失,临床符合JBS,均表现有严重脑发育迟缓、小头畸形和面容异常,均无血小板减少。病例1为低出生体重儿,同时患脑白质髓鞘化延迟;病例2合并先天性心脏病并有骨骼畸形。2例患儿11号染色体缺失片段长度分别为4.1Mb和12.8Mb,其中4.1Mb是目前报道的最小缺失区域。结论　JBS导致DD/MR的关键区域可能位于接近亚端粒区4.1Mb范围内,SNX19、THYN1、OPCML、NCAPD3 和NTM可能为其关键的致病基因;导致颅面部畸形的重要区域可能位于在11号染色体上130.3～134.4Mb区域;导致心脏结构异常的关键区域可能位于125.8～130.4Mb区域。其基因型与表型的确切关系,还有待大样本分析并确认导致DD/MR的致病基因。     

Detection of KAL-1 gene deletion with fluorescence in situ hybridization.

We investigated the molecular cytogenetic status of two unrelated boys and their family members because they had features consistent with Kallmann syndrome but normal karyotypes. The first patient was a 6-year-old boy who suffered from ichthyosis, bilateral cryptorchidism, hyposmia, and neurologic disorders including mirror movements of the hands and nystagmus. Mild to moderate mental retardation was also noted in this boy, his mother, and maternal grandmother. Fluorescence in situ hybridization (FISH) study using probes for Kallmann (KAL), steroid sulfatase, and ocular albinism type 1 all showed nullisomy on Xp22.3 in this patient, and hemizygosity in his older sister, mother, and maternal grandmother. The second patient was a 1-year-old boy who had micropenis, cryptorchidism, and hypoplastic scrotum since birth. Family study disclosed a 28-year-old maternal uncle with cryptorchidism, lack of secondary sexual characteristics, and anosmia. FISH showed only the KAL gene deletion. Polymerase chain reaction analysis also showed an absence of the KAL-1 sequence. FISH is a useful tool for the detection of KAL-1 deletion in people with normal karyotypes but features consistent with Kallmann syndrome.     

A patient with de-novo partial deletion of Xp (p11.4-pter) and partial duplication of 22q (q11.2-qter)

We report on a girl with partial deletion of Xp and partial duplication of 22q. Family studies demonstrate that both the patient's mother and her nonidentical twin sister carry the corresponding balanced translocation; 46,X,t(X;22)(p11.4;q11.2). This girl has developmental delay, microcephaly, mild dysmorphisms and hearing loss but otherwise shows few of the features described in individuals with duplications of the long arm of chromosome 22. She does manifest characteristics, such as short stature and biochemical evidence of ovarian failure, which are seen in partial or complete Xp deletions and Turner's syndrome.     

Breastfeeding and vegan diet

Vegan diet in lactating women can induce vitamin B12 deficiency for their children with risk of an impaired neurological development. A 9.5-month-old girl presented with impaired growth and severe hypotonia. She had a macrocytic anemia secondary to vitamin B12 deficiency. MRI showed cerebral atrophy. She was exclusively breastfed. Her mother was also vitamin B12 deficient, secondary to a vegan diet. She had a macrocytic anemia when discharged from the maternity. Vegan diet is a totally inadequate regimen for pregnant and lactating women, especially for their children. Prevention is based on screening, information and vitamin supplementation.     

Semilobar holoprosencephaly prenatal diagnosis: an unexpected complex rearrangement in a de novo apparently balanced reciprocal translocation on karyotype

We report a semilobar holoprosencephaly (HPE) in a post-intracytoplasmic-sperm-injection pregnancy. It was suggested by ultrasonography (US), documented on karyotype, identified with magnetic resonance imaging (MRI), established after birth and confirmed on post-mortem autopsy. An amniocentesis revealed a de novo apparently balanced reciprocal translocation 46,XY, t(7;8) (q31.3;q12). Fluorescence in situ hybridization (FISH) identified a deletion in the region of the Sonic Hedgehog gene (SHH) on der(8); nevertheless, the subtelomeric regions for chromosomes 7 and 8 were present. The parents decided to continue the pregnancy; a boy was born and survived for 3 days. The brain autopsy confirmed the semilobar HPE previously noted on US and MRI. Further, band-specific FISH revealed, in addition to SHH deletion, the presence of an inversion in the 7q translocated material on der(8). The parents' karyotypes were normal. An unexpected complex rearrangement was present in a de novo apparently balanced reciprocal translocation in a semilobar HPE.     

新一代测序技术确诊1例遗传多囊肾病家系

目的明确1例肝肾发育异常患儿的遗传学病因。方法收集该患儿的家族史及临床资料,抽取患儿及其父母外周静脉血2 mL,对患儿基因组DNA进行新一代测序分析,并对疑似致病性突变位点进行Sanger测序验证及生物信息学预测。结果该患儿系第三胎第一产,前2胎均在围产期死亡,B超示多囊肾表现。该患儿为男性,4月大,腹部膨隆可触及质硬包块,腹部超声提示多囊肾并肝纤维化,新一代测序显示患儿PKHD1基因第30外显子c.3500TC(p.L1167P)杂合突变,遗传自母亲;另外患儿PKHD1基因第58外显子c.9235_9236del GCins AA(p.A3079K)杂合突变,来自父亲;父母表型均正常,这2个突变均为新发现的突变。结论该患儿是由PKHD1基因的复合杂合突变导致的常染色体隐性遗传多囊肾病(ARPKD),结合家族史推断,该家系前2胎可能同样患有ARPKD。新一代测序可对该类疾病明确诊断,并有助于遗传咨询,以避免该类悲剧的再次发生。     

Monosomy 5p and trisomy 12p in a boy with familial balanced translocation

We report on a boy with monosomy 5p involving the Cri-du-Chat critical region and trisomy 12p detected by subtelomere study. Familial studies showed that the boy's mother and paternal grandfather had a balanced reciprocal translocation between the short arm of chromosomes 5 and 12. The boy had an overlap of features of both chromosomal conditions, even though the Cri-du-Chat phenotype was more prominent.