Maternal uniparental disomy 14 dissection of the phenotype with respect to rare autosomal recessively inherited traits, trisomy mosaicism, and genomic imprinting

Maternal uniparental disomy 14 dissection of the phenotype with respect to rare autosomal recessively inherited traits, trisomy mosaicism, and genomic imprinting

Annales de Génétique 47 (2004) 251–260 www.elsevier.com/locate/anngen Maternal uniparental disomy 14 dissection of the phenotype with respect to rare...

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Annales de Génétique 47 (2004) 251–260 www.elsevier.com/locate/anngen

Maternal uniparental disomy 14 dissection of the phenotype with respect to rare autosomal recessively inherited traits, trisomy mosaicism, and genomic imprinting Dieter Kotzot * Institute of Medical Biology and Human Genetics, Medical University of Innsbruck, Schoepfstr. 41, A-6020 Innsbruck, Austria Received 15 January 2004; accepted 25 March 2004 Available online 10 May 2004

Abstract The phenotype of maternal uniparental disomy of chromosome 14 (upd(14)mat) is characterized by pre and postnatal growth retardation, early onset of puberty, joint laxity, motor delay, and minor dysmorphic features of the face, hands, and feet. Based on a clinical analysis of 24 cases extracted from the literature the phenotype of upd(14)mat was dissected with respect to each symptom’s most likely primary causative: trisomy mosaicism, rare autosomal recessively inherited traits, and the impact of known imprinted genes located on chromosome 14q32. As a result, primary factors are confined placental mosaicism for prenatal growth retardation and one or more imprinted genes, which contribute to the reduced final height by accelerated skeletal maturation. As a secondary effect the latter might also cause early onset of puberty. Other secondary effects might be postnatal adaptation problems associated with neurological deficits such as muscular hypotonia due to premature delivery and reduced birthweight and most dysmorphic features as a consequence of subtle skeletal abnormalities and muscular hypotonia. Considering the rarity of traits such as cleft palate, trisomy mosaicism in the fetus is more likely causative than homozygosity of autosomal recessively inherited mutations. Totally, the variable phenotype of upd(14)mat is mainly the consequence of trisomy mosaicism and genomic imprinting. Rare traits might be due to homozygosity of autosomal recessively inherited mutations. © 2004 Elsevier SAS. All rights reserved. Keywords: Genomic imprinting; Heterodisomy; Isodisomy; Maternal uniparental disomy 14

* Tel.: +43-512-507-3464; fax: +43-512-507-2861. E-mail address: [email protected] (D. Kotzot). © 2004 Elsevier SAS. All rights reserved. doi:10.1016/j.anngen.2004.03.006

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1. Introduction Maternal uniparental disomy 14 (upd(14)mat) describes the inheritance of both chromosomes 14 only from the mother and none from the father. The first case was reported by Temple et al. [37] in 1991. The 17-year-old male patient was affected by pre and postnatal growth retardation, hydrocephaly, early onset of puberty, and minor dysmorphic features. Mental development was normal. Genetic investigations revealed a 45,XY,der(13;14) (q10;q10)mat karyotype and heterodisomic upd(14)mat. The latter indicated that both maternal homologs were present, either in part or entirely. Meanwhile, clinical, cytogenetic, and molecular details of 24 cases with complete upd(14)mat have been reported [1–3,7,8,11,14–16,18,20,24,25,28,30,31,33–35,37–40]. Recently, Sutton and Shaffer [36] delineated a phenotype of pre and postnatal growth retardation, precocious puberty, joint laxity, motor delay, and minor dysmorphic features of the face, hands, and feet. However, the exact reason(s) for this clinical picture as a whole or for a single symptom has not been definitely clarified so far. Here, a review of the phenotype of upd(14)mat is followed by a thorough examination of each symptom with respect to its most plausible cause: trisomy mosaicism, homozygosity of rare autosomal recessively inherited mutations, or genomic imprinting.

2. Methods and results An extensive study of the literature resulted in molecular and clinical data on 24 cases with complete upd(14)mat [1–3,7,8,11,14–16,18,20,24,25,28,30,31,33–35,37–40]. Further case reports, that did not mention clinical details, were not considered. In seven out of the 24 cases, molecular investigations indicated isodisomy [24,30,35,38,39]. In some of these cases only few markers were analyzed. In addition, some isodisomic cases might be really heterodisomic due to double recombination not detected even though many markers had been investigated. In 17 cases heterodisomy was recorded [1–3,7,8,11,14–16, 18,20,24,28,34,37,40]. In addition, two cases with heterodisomic interstitial segmental upd(14)mat were reported [9,26], but recently, one of them was scrutinized by further molecular investigations [6]. Clinical features and results of chromosome analysis of all 24 cases were listed in Tables 1–2 and compared with each other in Table 3. Only the trait “hyperextensible joints” showed a weak statistical significance (v21;0.95, t-test). Dysmorphic features described in detail in 14 patients (five isodisomic, nine heterodisomic, and one segmental heterodisomic) are listed separately in Table 4 [1,3,7–9,16,18,25,28,30,33,37–39]. The pattern of dysmorphisms is subtle and only weak diagnostic criteria could be delineated. The age at diagnosis varied between 3 months and 26 years of age. Hydrocephaly diagnosed in four heterodisomic cases was self-limited and in no case a surgical treatment was necessary [1,16,30,37]. Weight was normal or below the 10th percentile in infancy, but later in life obesity becomes a typical feature. Psychomotor development and intelligence were described by general terms like “normal”, “retarded”, or “delayed”. In only three cases the IQ was tested and reported as being in the lower normal range or slightly below [1,25,34].

Table 1 Cytogenetic and clinical features of patients with maternal uniparental heterodisomy 14 (n = 17)

Maternal age (years) Gestation (weeks) Birth length (cm)

32

Birth weight (g) Birth OFC (cm) Hypotonia Hydrocephaly Last examination (age) Height (cm)

Antonarakis et al. [1] 45,XX, der (13;14) (q10;q10)/ 46,XX, +14,der (13;14) (q10;q10) dn 24 32–33

Healey et al. [16] 45,XX, der (13;14) (q10;q10) dn

1430 (P25) 28 (P10)

1759 (P25)

2000 (
– + 17 years

+ + 9 years

154 (
110.5 (
– + 43/12 years P3 P3

Mild

Weight (kg) OFC (cm)

Barton et al. [2] 45,XX, der (13;14) (q10;q10)/ 46,XX, +14,der (13;14) (q10;q10) dn

30 38

Coviello et al. [7] 45,XX, der (13;14) (q10;q10) dn

Link et al. [24] 45,XY, der (13;14) (q10;q10) mat

Desilets et al. [8] 45,XX, der (13;14) (q10;q10) mat

Harrison et al. [15] 45,XY, der (13;14) (q10;q10) mat

32 40

Miyoshi et al. [27] 45,XY, der (14;14) (q10;q10) (triplets)

32 29 31* Low

634*

Berends et al. [3] 45,XY, der (14;21) (q10;q10) mat

Berends et al. [3] 45,XY, der (14;14) (q10;q10) dn

40 46 (
40


25.6*

Developmental delay

Motor

Mild

Intelligence

Normal

Small hands Hyperextensible joints Scoliosis Early onset of puberty

+ –

Normal (IQ 86) + +

+ 10 years

Advanced bone age Recurrent otitis media Hypercholesterolemia Obesity Dysmorphic features a Others

+ + – + + Bifid uvula

+

1 year

+ – 13 months 12 years

+ – 13 years

+



+

3 years

+ – 9 months

+ – 7 years

+ – 3 months

+

59.3*

57 (P10)

41*

107 (P97) 51 (P50)

+

Motor

Normal

P75

4210*

Normal Retarded

Motor

Motor



Retarded

Normal

Normal

Normal

+

+ +

+ +

+

+ 9 years



+

+ + + +

+ +

+

+

Hypogonadism

+

– + + – – + +

+ Cleft palate

+

+ PDA

Fokstuen et al. [11] 46,XX

Hordijk et al. [18] 46,XY

Sanlaville et al. [34] CVS: 47,XX, +14/46, XX AC: 46,XX

37 40 47 (
44 40 43 (
41 35 41 (
2250 (
1640 (
+

Giunti et al. [14] 45,XX, der (13;14) (q10;q10) dn

P10–25

Kayashima et al. [20] 45,XY, der (14;14) (q10;q10)/ 46,XY, +14,der (14;14) (q10;q10) dn 41

+

– 20 years

P25–50

44/12 years 96 (P3)

41 months 30 years
132 (
4 (
143 (
>P97

15 (P3)


39.5 (
52.5 (
P50

48.5 (
Normal

Delayed

Normal

Normal

+ +

+ +

+

– 811/12 years + – – +

+ +

+

9 years

Worley et al. [40] 45,XY, der (13;14) (q10;q10) ?

Motor Normal (IQ 87) +

Language Normal +



+ +

42 (
Normal

Retarded –

– –

+ Retarded


D. Kotzot / Annales de Génétique 47 (2004) 251–260

Karyotype

Temple et al. [37] 45,XY, der (13;14) (q10;q10) mat

+

+ MODY

253

AC = amniocentesis; CVS = chorionic villi sampling; dn = de novo; mat = maternal; MODY = maturity onset diabetes of the young; OFC = occipitofrontal head circumference; P = percentile; PDA = persistant ductus arteriosus; PD = prenatal diagnosis; * no percentiles are available for triplets. a Described in detail in Table 4.

Karyotype

2216 (
1900 (
+ – 20 years 144.4 (
+ – 29/12 years Short 44.5 (
Tomkins et al. [38] 45,XY,der (14;14) (q10;q10)dn 24 40 51 (P97) 67.5 (>P97) 56 (>P97) Motor Mildly retarded + – – 8 years

+ – +

– –

+ –

– +

+

+

+ Migraine cubitus MODY valgus

Rod monochromacy

Robinson et al. [32] 45,XY,der (14;14) (q10;q10)dn 36

Splitt et al. [35] 45,XX,der (14;14) (q10;q10)dn

+ 8 years

9 years

+

45 2000 (
Manzoni et al. [25] 45,XY,der (14;14) (q10;q10) 18 ? 2000

19 years 166 cm (P5) 85 (P75–90) 54.5 (P50) Delayed (IQ 75) +

Towner et al. [39] CVS: 47,XX, +14 blood: 46,XX 40 46 (P25) 2020 (
Papenhausen et al. [30] 45,XX,der (14;14) (q10;q10) 26 35 (P10–50) 1261 (P50) 25.5 (P50–90) + +

P25 Motor Normal + Too young

+ + Skin pigmenta- PDA, renal failure, tion changes, an- death at 51 days terior placed anus

CVS = chorionic villi sampling; dn = de novo, MODY = maturity onset diabetes of the young; OFC = occipitofrontal head circumference; P = percentile; PDA = persistant ductus arteriosus. a Described in detail in Table 4.

D. Kotzot / Annales de Génétique 47 (2004) 251–260

Maternal age (years) Gestation (weeks) Birth length (cm) Birth weight (g) Birth OFC (cm) Hypotonia Hydrocephaly Last examination (age) Height Weight OFC Developmental delay Intelligence Small hands Hyperextensible joints Scoliosis Early onset of puberty Advanced bone age Recurrent otitis media Hypercholesterolemia Obesity Dysmorphic features a Others

Pentao et al. [31] 45,XX,der (14;14) (q10;q10)dn 24 40

254

Table 2 Cytogenetic and clinical features of patients with maternal uniparental isodisomy 14 (n = 7)

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Table 3 Comparative summary of clinical findings described in maternal isodisomy and heterodisomy 14 Feature Sex (male/female) Maternal age (years) Birth length (cm) (P10) OFC (P10–P90) Developmental delay Normal intelligence Small hands Hyperextensible joints Scoliosis Early onset of puberty Advanced bone age Recurrent otitis media Hypercholesterolemia Obesity Dysmorphic features

Heterodisomy (n = 17) 9/8 35.1 (n = 8) 5/6 a 8/10 a 3/3 a 10/13 3/9

Isodisomy (n = 7)

Total (n = 24)

3/4 26.5 (n = 4) 1/3 5/6 2/3 5/5 1/6

12/12 31.5 (n = 12) 6/9 13/16 5/6 15/18 4/15

15/16 b 5/9 a 7/9 a 12/14 10/12 10/11 6/7 4/9 6/7 4/5 3/5 2/5 7 10

5/6 2/3 3/6 4/5 3/6 5/5 1/4 1/4 4/4 – 2/4 2/5 1 5

20/22 7/12 10/15 16/19 13/18 15/16 7/11 5/13 10/11 4/5 5/9 4/10 8 15

Statistical analysis a n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. s n.s. n.s. n.s. n.s. n.s.

n.s. = not significant; OFC = occipitofrontal head circumference; P = percentile; s = significant. a (v21;0.95) for heterodisomy versus isodisomy. b The case reported by Myioshi et al. [28] was excluded, because of a triplet pregnancy.

The findings of an isochromosome of the long arm of chromosome 14 or a Robertsonian translocation t(13;14), t(14;14), or t(14;21) in six isodisomic cases [25,30,31,33,35,38] as well as in 14 heterodisomic cases are noteworthy [3,7,8,12,14–16,20,24,28,37,40]. Robertsonian translocations are de novo in five cases [2,3,7,14,16] and of maternal origin in five cases [3,8,15,24,37]. Trisomy mosaicism was demonstrated in one isodisomic case [39] and in four heterodisomic patients [1,2,20,34].

3. Discussion The concept of UPD was introduced in medical genetics by Engel [10] in 1980. In an ongoing process more and more cases have been recorded (reviewed in [21,22]). Already in the first reports trisomy mosaicism, homozygosity of autosomal recessively inherited mutations, and genomic imprinting were recognized as the main problems associated with UPD. However, dissection in a single patient is extremely difficult, because in most cases a mix of two or even three of these problems must be considered. So far, many cases with UPD were ascertained by molecular investigations of the parents of patients with autosomal recessively inherited mutations. The case of upd(14)mat asso-

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Table 4 Dysmorphic features of patients with maternal uniparental disomy 14 (n = 15). Features noted by looking at the published photographs are in italics Report Isodisomy 14 Robinson et al. Tomkins et al. Manzoni et al. Towner et al. Papenhausen et al.

Heterodisomy 14 Temple et al. Antonorakis et al. Healey et al. Coviello et al. Desilets et al. Miyoshi et al. Hordjik et al. Berends et al. (case 1) Berends et al. (case 2) Segmental upd(14) Eggermann et al.

Dysmorphic features Large and protruding ears, shallow orbits, depressed nasal bridge, narrow and upturned nose [33] High forehead, prominent brows, large tip of the nose, small philtrum, macrognathia, dysmorphic ears [38] Synophrys, prominent nasal bridge, high arched palate [25] Short philtrum, dysmorphic ears, clinodactyly [39] Short neck, small thorax with wide spaced hypoplastic nipples, depressed nasal bridge, small dysmorphic ears, protruding philtrum, short palpebral fissures [30] Prominent forehead and supraorbital ridges, short philtrum, downturned corners of the mouth, high palate, bifid uvula [37] High palate [1] Frontal bossing, short philtrum, high palate [16] Frontal bossing, asymmetric face [7] Hypoplastic nails [8] High forehead, frontal bossing, low set ears, overlapping fingers, short nails [28] High forehead, short nose, anteverted nares, downturned corners of the mouth, tapering fingers, clinodactyly [18] High forehead, bitemporal narrowing, almond shaped palpebral fissures, short philtrum, downturned corners of the mouth, small mandible, short nails [3] Small mandible, high palate [3] Snub nose, hypoplastic mandible, low set and malrotated ears, clinodactyly [9]

ciated with rod monochromacy is a typical example [31]. In general, a high frequency of a trait in a cohort of patients is an argument against homozygosity of an autosomal recessively inherited mutation due to isodisomy. Otherwise, the frequency of this mutation and the resulting phenotype in the general population should also be high. Therefore, features common in upd(14)mat such as growth retardation are very unlikely to be caused by homozygosity of autosomal recessively inherited mutations. Vice versa, anomalies rarely observed in upd(14)mat such as a bifid uvula, cleft palate, persistent ductus arteriosus, or hypogonadism should be good candidate traits for autosomal recessive inheritance. However, both cleft palate and retrognathia have frequently been reported in cases with trisomy 14 mosaicism [12], and indeed low level trisomy 14 mosaicism has been found in the upd(14)mat case associated with cleft palate [2]. Persistent ductus arteriosus is a relatively common finding among small and premature infants. Heterodisomy is another argument against autosomal recessive inheritance, as otherwise, the mother should have been affected, too. However, the fact that meiotic recombinations resulting in isodisomic segments have not been detected, based on only a few markers, does not mean that heterodisomy is representative for the whole chromosome. Confined placental mosaicism as a specific form of trisomy mosaicism has widely been accepted as a major cause of prenatal growth retardation [19]. In cases with UPD it might

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be produced by either postzygotic non-disjunction or by fertilization of a disomic gamete by a monosomic gamete and subsequent loss of the single homolog in a proportion of cells (“trisomy rescue”). Robinson et al. [32] found a correlation of pregnancy outcome (usually intrauterine growth retardation) with the level of trisomy in the trophoblast. In the case of heterodisomic UPD due to trisomy rescue the likelihood of trisomy mosaicism is high. This might be not only in the four heterodisomic cases with proven trisomy mosaicism [1,2,20,34], but also in all other 13 patients with heterodisomy. In this context, the averagely high maternal age of 35.1 years in heterodisomic cases versus 26.5 years in isodisomic cases (Table 4) is of interest. Moreover, in one case with isodisomy born to a 40-year-old mother trisomy mosaicism has been reported [39]. If this is true, a complex mechanism of formation must be postulated implying either a maternal meiosis II nondisjunction lacking any previous recombination, or alternatively a biparental disomic zygote followed by either loss of the paternal homolog and subsequent somatic reduplication or non-disjunction of the maternal homolog followed by the loss of the paternal homolog (“postfertilization error”). Prenatal growth retardation is also reported in upd(14)pat [23] being a hint towards an unspecific etiology. In summary, confined placental mosaicism is the most likely cause for prenatal growth retardation in upd(14)mat. Fetal trisomy mosaicism not detected in routine investigations might also be relevant for developmental delay and/or low intelligence in some cases. Specific IQs were given in only three cases and were ranging between 75 and 87 [1,25,34]. As some cases with upd(14)mat show normal mental development (Tables 1 and 2), mental retardation should not be considered as a primary feature. The epigenetic phenomenon of genomic imprinting describes the expression of a gene in relation to its parental origin. Well known and clinically relevant instances are upd(11p15)pat in approximately 20% of cases with Beckwith–Wiedemann syndrome [17], upd(15)mat in approximately 30% of cases with Prader–Willi syndrome [4], and upd(15)pat in approximately 3–5% of cases with Angelman syndrome [4]. In the latter two cases the region of genomic imprinting has been mapped to a small segment on 15q11–q13. There, paternally as well as maternally imprinted genes are ordered in a cluster regulated by a common imprinting center [4]. A similar cluster of reciprocally imprinted genes and transcripts were recently described on 14q32 [5]. Each three out of six transcripts (DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8) were expressed from the maternal and paternal alleles, respectively. However, it is not clear so far, whether biallelic, and therefore, overexpression of one of the maternally expressed transcripts (GTL2, antiPEG11, and MEG8), lack of the product of one or more of the paternally expressed gene(s) (DLK1, PEG11), other at present unidentified genes, or even a combination of different (unknown) genes are relevant for (parts of) the phenotype of upd(14)mat. Overexpression of GTL2, which seems to have growth inhibitory effects [27], would explain acceleration of skeletal maturation and as a consequence the marked growth retardation. If this proves to be true postnatal growth retardation could be caused by genomic imprinting and early onset of puberty, which is a consequence of the accelerated skeletal maturation, would be a feature caused secondarily. In vitro the DLK1 protein can inhibit adipogenesis and in mice lack of the paternal allele causes growth retardation, obesity, and increased serum lipid metabolites [29]. Therefore, lack of the paternal gene product of DLK1 in human upd(14)mat might also cause these features.

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Not numerically quantifiable traits such as muscular hypotonia, motor delay, hyperextensible joints, or dysmorphic features should be discussed more generally. Motor delay as reported in six heterodisomic [3,7,18,24,37] and four isodisomic cases [31,33,38,39] and muscular hypotonia in 15 patients [1,3,7,8,15,18,24,28,30,31,33,38–40] might be in part secondary to problems in postnatal adaptation due to intrauterine growth retardation. In this context it is noteworthy, that a minimum of seven cases were delivered prematurely (Tables 1 and 2) [1,16,30,33,34,37,38]. If only dysmorphic features reported by the authors were considered (Table 4), only a subtle pattern of dysmorphisms (prominent forehead, high palate) could be delineated. Sutton and Shaffer [36] as well as Georgiades et al. [13] expanded the phenotypical findings on relevant features observed on published photographs and compared upd(14)mat with cases with various duplications or deletions of chromosome 14. They noted that a fleshy nasal tip was most often associated with dup(14)(q32) and a hirsute forehead and blepharophimosis with del(14)(q12q13.3) and del(14)(q32), respectively. However, it seems to be unlikely that one or several (imprinted) genes are specifically responsible for dysmorphic features. These anomalies are more likely secondary to subtle skeletal abnormalities or neurological problems. As so far only one case with segmental upd(14)mat has been reported [9], at time it is not possible to compare segmental upd(14)mat with complete upd(14)mat. In summary, the phenotype of upd(14)mat is characterized by symptoms such as pre and postnatal growth retardation caused by primary factors (trisomy mosaicism, genomic imprinting) and secondary features such as early onset of puberty, muscular hypotonia, and mild motor delay. Homozygosity of autosomal recessively inherited traits is of minor impact, except one of the parent is a carrier of an autosomal recessively inherited mutation.

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