Uniparental isodisomy 13 in a normal female due to transmission of a maternal t(13q13q)

Chromosomes from a normal 23-year-old, primigravid woman were examined at 10 weeks of gestation because of her mother's history: 8 miscarriages and two liveborn infants (the proposita and a brother who died at 3 days with multiple anomalies). Karyotypes of the proposita and her normal mother were 45,XX, t(13q13q). No evidence of mosaicism was encountered. When the proposita inherited the t(13q13q), she received two copies of 13q from her mother. Moreover, she and her mother shared the same homozygous pattern of alleles from 7 highly polymorphic microsatellite repeats localized along 13q. No evidence of paternal markers from 13 was detected, although biparental inheritance was demonstrated with DNA markers from chromosomes 2 and 17. Cytogenetic and molecular findings indicated that the proposita's chromosomal complement included mUPD 13q. The proposita's normal phenotype suggested that no maternally imprinted genes map to 13q. © 1995 Wiley-Liss, Inc.     

Partial 3p trisomy and different rearrangements involving chromosome 3 in the proposita's family

A case of partial 3p trisomy is reported here. A review of published cases (8 ♂, 2 ♀, 7 families) shows a characteristic pattern of anomalies, constituting one more syndrome of multiple congenital anomaly and mental retardation (MCA/MR) characterized by microcephaly, brachycephaly, frontal bossing, temporal indentation, square face, hypertelorism or telecanthus, epicanthus, short nose with a large tip, prominent cheeks, long and protruding philtrum, large and downturned mouth, protruding mid-upper lip, micro- or retrognathia, short neck, congenital heart defects, gastrointestinal malformation, penile hypoplasia, neuromotor or mental retardation, and predominance of whorls on digits. The proposita had a 46,XX,der(11),t(3;11)(p21;q25) karyotype. The mother was a carrier of a de novo 3;11 balanced translocation. Chromosome mosaicism was detected in a female sibling of the proposita: 46% of her cells were 46,XX and 54% had a 46,XX,t(3;20)(p21;q13) karyotype - ie, a de novo 3;20 balanced translocation. We discuss the origin of this mosaicism and the possible meaning of the breaks involving the same region of chromosome 3 (region 3p21) in the members of the proposita's family.     

Dominant inheritance of Kabuki make-up syndrome

We report on a total of 4 individuals in 2 families with Kabuki make-up syndrome. In family 1, the proposita, a 2 4/12-year-old girl and her mother had typical Kabuki make-up syndrome. The proposita also had early breast development. In family 2, the proposita, a 6-month-old girl and her mother had typical Kabuki make-up syndrome. The proposita died at age 6 months. Analysis of 2 families indicates that the condition is an autosomal dominant inheritance with variable expressivity. Am. J. Med. Genet. 73:19–23, 1997. © 1997 Wiley-Liss, Inc.     

Balanced rearrangement of chromosomes 2, 5, and 13 in a family with duplication 5q and fetal loss

We have studied a family in which a mother and daughter (the proposita) had the karyotype 46,XX,ins(2;5),t(5;13). The mother had four spontaneous abortions, a mentally retarded son with duplication (5q), and a daughter who died at 3 months. The proposita had a phenotypically abnormal abortus. Rearrangements involving several chromosomes are very rare. Observations on this family are consistent with the predicted high likelihood of reproductive loss.     

Familial interstitial deletion 11(p11.12p12) associated with parietal foramina,brachymicrocephaly, and mental retardation

Parietal foramina may be an isolated autosomal dominant trait or found in syndromes. We report on two related individuals who have multiple anomalies with parietal formaina and the deletion of 11(p11.12p12) due to the inheritance of a derivative chromosome 11 from an insertional translocation dir ins(13;11)(q14.1;p11.12p12). Results of initial chromosome analyses on the proposita and her maternal halfuncle were reported as normal. However, the clinical manifestations and family history suggested a chromosomal cause and cytogenetic studies were performed on the proposita's mother. A derivative chromosome 13 was initially identified and further evaluation documented a derivative 11 as the reciprocal product. This family illustrates the importance of performing chromosome studies on the normal intervening relatives in families with multiple affected individuals with mental retardation and minor anomalies as one of the two reciprocal products may be more easily detectable in a balanced carrier. Additionally, the finding of del(11)(p11.12p12) may provide a map location for a syndrome which includes parietal foramina. © 1993 Wiley-Liss, Inc.     

Familial occurrence of bifid femur and monodactylous ectrodactyly

Two brothers each hada one normal upper limb; one had tridactylous ectrodactyly of one hand with normal forearm bones; the other had monodactyly of one hand with absent ipsilateral ulna. Both had monodactyly of the feet, absence of the tibiae, and unilateral bifurcation of the femur. A sister of the paternal grandfather was purportedly similarly affected. Since her parents and the father and paternal grandfather of the affected boys were normal, the pattern of inheritance of the trait in this family is presently unclear.     

Trichorrhexis Nodosa and lip pits in autosomal dominant ectodermal dysplasia—central nervous system malformation syndrome

A Dandy-Walker-like malformation was observed in a retarded girl who had signs of hidrotic ectodermal dysplasia. This is the third report of the rare triad ectodermal dysplasia-CNS malformation-mental retardation. We observed additional findings, such as submucous cleft palate with lip pits and trichorrhexis nodosa. The proposita's mother had similar hair and facial changes. Two maternal relatives had cleft palate. Autosomal dominant inheritance is suggested. Am. J. Med. Genet. 71:226–228, 1997. © 1997 Wiley-Liss, Inc.     

Female haemophilia A in a family with seeming extreme bidirectional lyonization tendency: abnormal premature X-chromosome inactivation?

We studied a female child with mild classical haemophilia A, presenting with a F VIII deficiency similar to that detected in her maternal grandfather. Investigations on several occasions showed that the obligate carrier mother of the proposita had normal VIII:C activity, whereas her likewise obligate carrier sister had a typical carrier VIII:C/vWf:Ag pattern. The child was a phenotypically normal female with normal karyotype. Her father had no clinical or biochemical signs of haemophilia A. RFLP-analysis using DX13 and St14 probes each elicited one allele (5.8 and 3.4 kb, respectively) segregating along with the affected F VIII gene from the hemizygous grandfather to both his daughters and further to the haemophilic female child. The paternity of the child was analyzed using various red cell and HLA antigens and RFLP by p29C, a probe detecting polymorphic hypervariable TaqI and PstI fragments in the pseudoautosomal areas of the X- and Y-chromosomes. All results obtained were concordant with the declared paternity. RFLP-analysis, using single (Pst I) and double digestion (Pst I/Hha I) of DNA and a PGK probe, revealed a remarkable difference in hybridization fragments, strongly suggesting hypermethylation, and in consequence, preferential X-chromosome inactivation in the proposita. This points to extreme lyonization as the most plausible explanation for haemophilia A in this female child. A familial tendency to abnormal premature X-chromosome inactivation is speculated.     

Segregation of a familial balanced (12;10) insertion resulting in dup(10)(q21.2q22.1) and del(10)(q21.2q22.1) in first cousins

An interchromosomal insertion in 3 generations of a family was ascertained through two developmentally delayed first cousins. Cytogenetic analysis using G-banding and chromosome painting showed an apparently balanced direct insertion of chromosome 10 material into chromosome 12, ins(12;10)(q15;q21.2q22.1), in the mothers and grandfather of these children. The proposita inherited only the derivative 10 chromosome, resulting in deletion of 10q21.2 → 22.1 while her cousin inherited only the derivative 12, resulting in duplication of 10q21.2 → 22.1. A comparison of the proposita with published deletion cases suggests a pattern of anomalies attributable to deletion of the 10q21 → q22 region: developmental delay, hypotonia, a heart murmur, telecanthus, broad nasal root and ear abnormalities. This is the first report of a nontandem duplication of the 10q21 → q22 region. The phenotype of the cousin with the duplication does not overlap greatly with published tandem 10q duplications. Finally, this report reaffirms the importance of obtaining family studies of patients with interstitial chromosomal abnormalities. Am J. Med. Genet. 69:188–193, 1997. © 1997 Wiley-Liss, Inc.     

Spinocerebellar degeneration and cerebral hypomyelination in a family

The proband is a 24-year-old woman who developed symptoms of a spinocerebellar degeneration in early childhood. Neurological examination revealed normal cognitive function, optic atrophy, dysarthria, titubation, action tremors, increased deep tendon reflexes, Babinski's signs, and a spastic scissoring gait. The magnetic resonance imaging (MRI) showed an abnormal increased signal on long TR images involving white matter throughout the cerebral hemispheres, most striking in the subcortical white matter, and to a lesser degree in the brainstem, compatible with diffuse hypomyelinating or dysmyelinating diseases. Metabolic and chromosomal studies were normal. Her 49-year-old mother developed similar symptoms in her 20s and is now wheelchair-bound. Findings on neurological examination and MRI were similar to her daughter but more severe. The proband's maternal grandfather had a female cousin who had a neurological illness beginning in her 20s with similar symptoms and signs and died at the age of 44 years. Spinocerebellar degenerations are a group of syndromes with similar clinical manifestations but heterogeneous etiology. We report a family with spinocerebellar degeneration with distinct MRI findings compatible with hypomyelination or dysmyelination which has not heretofore been described. This family may represent a new spinocerebellar syndrome due to an abnormality of as yet an undetermined gene. © 1995 Wiley-Liss, Inc.     

Compound heterozygous mutations in KvLQT1 cause Jervell and Lange-Nielsen syndrome

Jervell and Lange-Nielsen syndrome (JLNS) is characterized by sensorineural deafness, QT prolongation, abnormal T waves, ventricular tachyarrhythmias, and autosomal recessive inheritance. Previously homozygous mutations in the potassium channel-encoding genes, KvLQT1 (alpha-subunit) and KCNE1 (beta-subunit), have been described in consanguineous families with JLNS. We screened two nonconsanguineous families with JLNS for mutations in KvLQT1, using single-strand conformation polymorphism analysis, denaturing high-performance liquid chromatography, and DNA sequencing. In one family, a missense mutation was identified in exon 6 of KvLQT1 on the maternal side, resulting in a glycine to aspartic acid substitution at codon 269 (G269D). The apparently normal father had an incompletely penetrant missense mutation in exon 3 of KvLQT1, introducing a premature stop codon at position 171. In the other family, a missense mutation resulting in the substitution of asparagine for aspartic acid at codon 202 (D202N) was identified in the mother and maternal grandmother, who had QTc prolongation (borderline in the mother), while the father and paternal grandfather, who were clinically normal, had a deletion of nucleotide 585, resulting in a frameshift and premature termination. In both families, the proband inherited both mutations. In this report we provide evidence that not only homozygous but also compound heterozygous mutations in KvLQT1 may cause JLNS in nonconsanguineous families. Incomplete penetrance in individuals with mutations appears to be frequent, indicating a higher prevalence of mutations than estimated previously. Interestingly, mutations resulting in truncation of the protein appear to be benign, with heterozygous carriers being asymptomatic.     

Miller-Dieker syndrome and trisomy 5p in a child carrying a derivative chromosome with a microdeletion in 17p13.3 telomeric to the LIS1 and the D17S379 loci

Trisomy 5p and Miller-Dieker syndromes frequently are the result of unbalanced segregations of reciprocal translocations of chromosomes 5 and 17 with other autosomes. The critical regions for the expression of the mentioned syndromes have been mapped to 5p13→pter, and 17p13.3→pter. In this report, we describe an 8-year-old girl with mental retardation, postnatal growth deficiency, generalized muscular hypotonia, seizures, microcephaly, cortical atrophy, partial agenesis of corpus callosum, cerebral ventriculomegaly, facial anomalies, patent ductus arteriosus, pectus excavatum, long fingers, and bilateral talipes equinovarus caused by the presence of a 46,XX,der(17)t(5;17)(p13.1;p13.3)mat chromosome complement. Cytogenetic studies of the family confirmed a balanced reciprocal translocation (5;17)(p13.1;p13.3) in her mother, maternal grandfather, maternal aunt, and a female first cousin. Fluorescence in situ hybridization studies on the mother and the proposita using three probes, which map to distal 17p, confirmed the reciprocal translocation in the mother and a terminal deletion in the patient, which resulted in the retention of LIS1 and D17S379 loci and deletion of the 17p telomere. These findings and the phenotype of the proposita, strongly suggest that genes telomeric to LIS1 and locus D17S379 are involved in many clinical findings, including the minor facial anomalies of the Miller-Dieker syndrome. Am. J. Med. Genet. 85:99–104, 1999 © 1999 Wiley-Liss, Inc.     

Duplication of Xq26.2-q27.1, including SOX3, in a mother and daughter with short stature and dyslalia

Duplications of the distal long arm of the X chromosome are rare and carrier females are usually phenotypically normal. We report on a 14-year-old short statured (height and weight <3rd centile) girl with dup(X)(q26.2q27.1) inherited from a short mother. The proband has minor dysmorphic features, lordosis, lack of menarche, late signs of puberty, low prepuberal levels of gonadotrophins and steroids, but borderline low IGF-1 and normal IGF-Bp3 serum levels. Both the proposita and her mother have severe speech problems with stuttering and dyslalia. The 44-year-old mother with a strikingly aged face and a prominent nose, had menarche at 15 years. Both maternal sisters and the grandmother of the proposita are also short. Karyotyping revealed an additional band at Xq26 in all metaphases from the proband, her mother, and two maternal aunts. Molecular cytogenetic investigations revealed an Xq26.2-q27.1 direct duplication of approximately 7.5 Mb that encompasses or disrupts the SOX3 gene, which maps at the distal border of the duplicated segment. A similar chromosomal duplication was reported recently in five families and in each was associated with an abnormal phenotype in males with short stature [Hol et al., 2000; Solomon et al., 2002, 2004]. Using an androgen-receptor (HUMARA) gene methylation assay and FISH, we show that despite preferential inactivation of the dup(Xq) chromosome a significant proportion of lymphocytes in both mother and daughter carry an active duplicated X chromosome. Our findings further suggest that a dosage effect of SOX3 may to be responsible for a speech disorder in addition to short stature secondary to hypopituitarism.     

Unbalanced translocation in a mother and her son in one of two 5;10 translocation families

We present two families with different distal long arm 5;10 translocations. In one family the propositus and his mother inherited the same derived chromosome 10 from the maternal grandfather who has a balanced t(5;10)(q35.3;q26.13). The phenotype of both the affected patients is milder and only partially overlaps with that of previous cases of distal 10q deletion. Other previously reported cases of transmitted imbalance are also remarkable for mild phenotype, occurrence of deletions rather than duplications and a strong bias toward maternal as opposed to paternal transmission. In the second family, the propositus inherited a derived chromosome 10 from his mother who carries a balanced t(5;10)(q35.1;q26.3) translocation; his clinical manifestations are consistent with an emerging phenotype for distal 5q duplications. © 1996 Wiley-Liss, Inc.     

Segregation of a t(1;3) translocation in multiple affected family members with both types of adjacent-1 segregants

A subtle balanced translocation involving the terminal regions of 1q and 3p was identified in a large family by high-resolution karyotype analysis and confirmed by fluorescence in situ hybridization (FISH) analysis. In this family, segregation of a balanced t(1:3)(q42.3;p25) chromosome translocation led to two types of viable unbalanced complements. The proband inherited the derivative chromosome 3, resulting in partial trisomy of 1q and partial monosomy of 3p. A paternal uncle and cousin had the reciprocal rearrangement with a derivative of chromosome 1, resulting in partial monosomy for 1q and partial trisomy for 3p. While profound mental and physical retardation and congenital heart defects were characteristics for both rearrangements, facial dysmorphism was quite distinct for each imbalance. Individuals who had the derivative chromosome 3 had a long face, wide eyebrows, small palpebral fissures, hypertelorism, prominent glabella, a large tip of the nose, long philtrum with thin upper lip, and low set-ears. In contrast, family members with the derivative of chromosome 1 had a tall forehead with bifrontal narrowing, full and large cheeks, and large simple ears. Since the translocated segments are small and approximately equal in size in this family, it is not surprising that viability was seen in individuals with both types of adjacent-1 segregation. In this kindred, the ratio of normal to abnormal individuals born to balanced carriers is believed to be about 1:1.5. This suggests that the recurrence risk for carriers is 50%.     

Submicroscopic deletion in cousins with Prader‐Willi syndrome causes a grandmatrilineal inheritance pattern: Effects of imprinting

The Prader‐Willi syndrome (PWS) critical region on 15q11–q13 is subject to imprinting. PWS becomes apparent when genes on the paternally inherited chromosome are not expressed. Familial PWS is rare. We report on a family in which a male and a female paternal first cousin both have PWS with cytogenetically normal karyotypes. Fluorescence in situ hybridization (FISH) analysis shows a submicroscopic deletion of SNRPN, but not the closely associated loci D15S10, D15S11, D15S63, and GABRB3. The cousins' fathers and two paternal aunts have the same deletion and are clinically normal. The grandmother of the cousins is deceased and not available for study, and their grandfather is not deleted for SNRPN. DNA methylation analysis of D15S63 is consistent with an abnormality of the imprinting center associated with PWS. “Grandmatrilineal” inheritance occurs when a woman with deletion of an imprinted, paternally expressed gene is at risk of having affected grandchildren through her sons. In this case, PWS does not become evident as long as the deletion is passed through the matrilineal line. This represents a unique inheritance pattern due to imprinting. Am. J. Med. Genet. 92:19–24, 2000. © 2000 Wiley‐Liss, Inc.     

Frontonasal dysostosis in two successive generations

Frontonasal dysostosis (also called frontonasal "dysplasia") comprises ocular hypertelorism, median facial cleft affecting nose and/or upper lip, unilateral or bilateral cleft of the alae nasi, anterior cranium bifidum occultum, or a widow's peak. Usually it is a sporadic disorder, although a few familial cases have been reported. We describe a 2-year-old girl with anterior cranium bifidum occultum, lipoma of genu and anterior part of the corpus callosum, and hypertelorism. Her mother had a history of a nasal drip at birth caused by a defect in the cribriform plate and phenotypically, a widow's peak. This observation suggests either autosomal dominant or X-linked dominant inheritance. The family illustrates the importance of identifying mild expression of frontonasal dysostosis before genetic counseling.     

Fetal loss and familial chromosome 1 translocations.

A structural abnormality of chromosome No. 1 was found in two families who had a history of repeated abortions. The propositus in Family H was a low birth weight, malformed infant who had a partial trisomy of 1g. His mother and a sibling were balanced carriers of a t(1;4) (q25;135). In family B, the 29-year-old phenotypically normal propositus and his mother were found to be balanced carriers of a t(1;12) (p12;q24). It is suggested that the fetal wastage in both families was related to the abnormal karyotypes of the parents. These two families also provide an opportunity to further understand the effect of an abnormality of chromosome number 1 on phenotype.     

Submicroscopic deletion in cousins with Prader-Willi syndrome causes a grandmatrilineal inheritance pattern: effects of imprinting

The Prader-Willi syndrome (PWS) critical region on 15q11-q13 is subject to imprinting. PWS becomes apparent when genes on the paternally inherited chromosome are not expressed. Familial PWS is rare. We report on a family in which a male and a female paternal first cousin both have PWS with cytogenetically normal karyotypes. Fluorescence in situ hybridization (FISH) analysis shows a submicroscopic deletion of SNRPN, but not the closely associated loci D15S10, D15S11, D15S63, and GABRB3. The cousins' fathers and two paternal aunts have the same deletion and are clinically normal. The grandmother of the cousins is deceased and not available for study, and their grandfather is not deleted for SNRPN. DNA methylation analysis of D15S63 is consistent with an abnormality of the imprinting center associated with PWS. "Grandmatrilineal" inheritance occurs when a woman with deletion of an imprinted, paternally expressed gene is at risk of having affected grandchildren through her sons. In this case, PWS does not become evident as long as the deletion is passed through the matrilineal line. This represents a unique inheritance pattern due to imprinting.     

Paracentric inversion of chromosome 19 in three generations

We observed a paracentric inversion of 19p in a 15-month-old white boy with developmental delay and mild facial anomalies. The inversion of 19p was also present in his phenotypically normal mother and maternal grandfather.