RESEARCH LETTER
A Novel Mutation in RNU4ATAC in a Patient with Microcephalic Osteodysplastic Primordial Dwarfism Type I Esra Kilic,1* Go¨khan Yigit,2,3,4 Gu¨len Eda Utine,1 Bernd Wollnik,2,3,4 Ercan Mihci,5 Banu Gu¨zel Nur,5 and Koray Boduroglu1 1
Faculty of Medicine, Division of Pediatric Genetics, Hacettepe University, Ankara, Turkey Institute of Human Genetics, University of Cologne, Cologne, Germany
2 3
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
4
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany Faculty of Medicine, Division of Pediatric Genetics, Akdeniz University, Antalya, Turkey
5
Manuscript Received: 3 July 2014; Manuscript Accepted: 21 December 2014
TO THE EDITOR: Microcephalic osteodysplastic primordial dwarfism type I (MOPD I; OMIM 210710), also named Taybi–Lindner syndrome, is a rare autosomal recessive disorder first described by Taybi and Linder [1967]. It is characterized by severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, bone dysplasia, brain malformations, hearing and vision impairment, and death occurs in infancy or early childhood. This disorder is distinguished from other microcephalic primordial dwarfism syndromes (e.g., MOPD II) by the presence of severe brain malformations, hyperkeratotic skin, and visual and hearing impairment [Winter et al., 1985; Meinecke and Passarge, 1991; Taybi, 1992]. In 2011, two studies identified mutations in the RNU4ATAC gene causing MOPD I [Edery et al., 2011; He et al., 2011]. RNU4ATAC (NG_029832.1) encodes a small nuclear RNA, U4atac, which is a crucial component of the minor U12-dependent spliceosome, and mutations in U4atac lead to decreased activity of the minor spliceosome, which is essential for splicing of about 800 U12type introns of genes of the human genome. Genes containing U12-type introns are involved in a broad variety of cellular processes including DNA replication and repair, RNA processing, and cytoskeletal organization, and defects in U12-dependent splicing can disrupt global cellular functions like proliferation, differentiation and cell growth [Edery et al., 2011; He et al., 2011]. To date, nine distinct mutations in RNU4ATAC among 40 patients with MOPD I have been described [Abdel-Salam et al., 2013]. Here we have identified a novel homozygous mutation in RNU4ATAC in a patient presenting with common features of MOPD I and, additionally, we document the rare phenotypic spectrum of MOPD I. The index patient, a 10-month-old boy on admission, was born as the second child to healthy first-degree cousins. His sister was healthy and there was no family history of any other genetic disease. He was born at 37th weeks of gestation by spontaneous vaginal delivery. During pregnancy, intrauterine growth retardation after the 20th week of gestation and pregnancy-induced hypertension
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Kilic E, Yigit G, Utine GE, Wollnik B, Mihci E, Nur BG, Boduroglu K. 2015. A novel mutation in RNU4ATAC In a patient with microcephalic osteodysplastic primordial dwarfism type I. Am J Med Genet Part A 167A:919–921.
were recorded. Amniocentesis showed a normal, 46,XY karyotype. Birth weight was 1335 g, length and OFC were not recorded. After birth, he had an infected urachal cyst excision. When he was clinically investigated at 10 months of age his weight was 4100 g (5.5 SD), length was 51 cm (7.3 SD) and OFC was 33 cm (10 SD). He had dry, hyperkeratotic skin diagnosed as lamellar ichthyosis, prominent metopic ridge, prominent eyes, sparse frontal scalp hair and eyebrows, a prominent nose with a bulbous tip, anteverted nares, long philtrum, thickened upper lip, mild retrognathia, and small ear lobules. Furthermore, he presented with short limbs, spade-like short hands with tapering fingers, edema and loose skin on hands, short feet with dorsal lymphedema, joint contracture on knees, short toes, small phallus with bilateral Funding/Conflict of interest: The authors declared no potential conflicts of interest. Our institutions consider this study in the realm of routine clinical care. Correspondence to: Esra Kilic, MD, Department of Pediatrics, Division of Pediatric Genetics, Hacettepe Univercity Ihsan Dog˘ramaci Children Hospital, Sihhiye, 06100, Ankara / Turkey. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 3 March 2015 DOI 10.1002/ajmg.a.36955
919
920 cryptorchidism, and a small scrotum (Supplemental Online Fig. 1). Neurological examination showed hypotonia with brisk reflexes. He was unable to control his head, had poor visual function and was not able to track his mother. During physical examination he showed only minimal interaction with environment, and his high squeaky nasal voice was remarkable. Ophthalmologic examination showed bilateral dense cataracts. Hearing tests showed bilateral sensorineural deficits. Abdominal and renal ultrasonography were normal. Echocardiography showed a small atrial septal defect. Skeletal radiologic examination showed small skull, short long bones, metaphyseal flaring, thin ribs, short metacarpals, small terminal phalanges, small iliac wings, horizontal acetabular fossae, absent ossification centers of the humeral heads and carpals (Supplemental Online Fig. 2). Magnetic resonance imaging (MRI) of the brain showed small frontal and parietal lobes, increased cerebrospinal fluid, simplified gyral pattern, small of the corpus callosum involving mainly the body and the splenium, and a small vermis (Supplemental Online Fig. 3). Routine laboratory tests including thyroid function tests and metabolic tests were normal, serological tests for intrauterine infections were negative. Chromosomal breakage studies utilizing diepoxybutane were normal. Within the first 12 months of age he had two episodes of pneumonia, and at 16 and 18 months of age, he had two episodes of bloody diarrhea. During these, he was febrile (39.5˚C–40˚C), had vomiting and mild hepatic failure with elevated liver enzymes. Due to recurrent infections, immunologic testing was performed showing moderate to significant reduction of total Immunoglobulin G level (387 mg/dl). Therefore, regular intravenous immunoglobulin therapy was started. At 19 months of age his weight was 4,800 g (4.6 SD), length was 57 cm (6.5 SD), and OFC was 34.5 cm (9.7 SD). He presented with a high, squeaky, nasal voice and frequent smiling. Despite hydration therapy, he still had dry, scaling skin. At 20 months of age he had a cataract operation following which he started to track his mother and to reach objects. At the most recent evaluation, he was 3 years old. Although he still showed marked developmental delay with poor head control and inability to sit without support, he was currently a sociable baby with frequent smiling. The diagnosis of MOPD I was made at 10 months of age based on clinical and skeletal findings in the patient. Genomic DNA of both parents and the index patient was screened for mutations in RNU4ATAC and Sanger-sequencing showed a novel, homozygous variant, g.46G>A, in the index patient. This variant was not annotated in dbSNP139 or the 1,000 Genomes Database, and both parents were heterozygous carrier for this alteration in RNU4ATAC (Supplemental Online Fig. 4). To date, only 40 patients with MOPD I with nine distinct mutations in RNU4ATAC have been described [Abdel-Salam et al., 2013]. This is a rare developmental disorder belonging to the spectrum of microcephalic primordial dwarfism (MPD) syndromes. Whereas all types of MPD show severe pre- and postnatal growth retardation, marked microcephaly and bone dysplasia, MOPD I is distinguished from other MPD syndromes based on severe brain anomalies and dry skin observed in affected patients [Majewski et al., 1982]. Furthermore, patients with MOPD I show a more severe global developmental delay and have a reduced life expectancy compared to other forms MPD, which lies in average around 8.5 months [Abdel-Salam et al., 2013]. The patient described
AMERICAN JOURNAL OF MEDICAL GENETICS PART A here showed all major findings of MOPD I (Supplemental Online Fig. 1). However, we did not observe seizures, kidney abnormalities, abnormal pigmentation or vasculopathy, which have been reported in MOPD I [Abdel-Salam et al., 2011; Pierce and Morse, 2012; Abdel-Salam et al., 2013]. Interestingly, the current patient presented with cataracts, which have only been reported once [Vichi et al., 2000], and hypogammaglobulinemia that, so far, was not observed in patients with MOPD I. Since it is reported that nearly half of the patients with MOPD I die due to infectious diseases [Abdel-Salam et al., 2013], the decreased serum immunglobulin G levels provide a possible explanation for the observed susceptibility to infections. Therefore, immunological profile should be considered when evaluating patients with MOPD I. The skeletal findings of the current patient are very similar to previously reported MOPD I patients. Radiological examination at the age of 10 months showed ridged metopic suture, short thinned cortex of long bones with metaphyseal broadening, delayed epiphyseal ossifications and hypoplastic phalanges. Further, the pelvis showed hypoplastic pubic bones and horizontal acetabular roofs (Supplemental Online Fig. 2). Cranial MRI of MOPD I patients show severe developmental brain malformations such as lissencephaly, poorly developed gyral pattern, malformed cerebrum with frontal pachygyria, enlarged ventricles, under myelinized white matter, thin corpus callosum and atrophic cerebellum [Pierce and Morse, 2012]. As a cardinal manifestation, almost all patients with MOPD I have partial or complete absence of the corpus callosum and 30% of reported patients have a small cerebellar vermis [Abdel-Salam et al., 2013]. Additionally, neuronal migration disorders are observed including pachygyria, lissencephaly, schisencephaly and polymicrogyria [Nagy et al., 2012]. At the age of 6 months, cranial MRI of the present patient showed small frontal lobes, simplified gyral pattern, small corpus callosum and vermis (Supplemental Online Fig. 3). To date, nine different mutations have been identified in the RNU4ATAC gene in patients with MOPD I, six of them, g.30G>A, g.50G>A, g.50G>C, g.51G>A, g.53C>G, g.55G>A, within the 50 stem loop and three of them, g.66G>C, g.111G>A, g.124G>A, located in the 30 stem loop of U4atac [Edery et al., 2011; He et al., 2011; Abdel-Salam et al., 2013]. Among these, the g.51G>A mutation is most frequently detected in patients with MOPD I. Although there is no obvious genotype-phenotype correlation, biallelic g.51G>A mutations have been associated with a shorter lifespan compared to other described mutations in RNU4ATAC [Nagy et al., 2012]. Compared to other primordial dwarfism syndromes, the prognosis of MOPD I is poor. The average life expectancy lies around 8.5 months, ranging from 2.5 to 18 months. Early death generally occurs within the first year of life and is mainly caused by infectious diseases. Up to date, the oldest patient reported died at 12.5 years of age due to pneumonia [Nagy et al., 2012]. The patient presented here in this study was 10 months of age when he was clinically evaluated, and is currently 3 years of age suggesting the possibility that the g.46G>A mutation might to be associated with longer survival. However, this conclusion is still preliminary and further patients with a similar mutation can confirm our assumption. The g.46G>A mutation lies within the 50 stem loop expanding the mutation spectrum in U4atac and underlining the importance of this structure for the function of U4atac. In silico modeling of U4atac structure using mfold predicts that the g.46G>A mutation
KILIC ET AL. drastically disrupts the 50 stem loop, which in wt U4atac is formed based on intramolecular base pairing within the U4atac snRNA (Supplemental Online Fig. 4B–C) [Zuker, 2003]. In conclusion, we report a newly described MOPD I patient carrying a novel mutation, g.46G>A, in RNU4ATAC. Presenting this additional patient and its phenotypic features may not only give a better understanding of the phenotypic variability within this disease, it will also provide further information for establishing a genotype-phenotype correlation in this rare disease and facilitate provision of accurate recurrence risks to families.
REFERENCES Abdel-Salam GM, Miyake N, Eid MM, Abdel-Hamid MS, Hassan NA, Eid OM, Effat LK, El-Badry TH, El-Kamah GY, El-Darouti M, Matsumoto N. 2011. A homozygous mutation in RNU4ATAC as a cause of microcephalic osteodysplastic primordial dwarfism type I (MOPD I) with associated pigmentary disorder. Am J Med Genet 155A:2885–2896. Abdel-Salam GM, Abdel-Hamid MS, Hassan NA, Issa MY, Effat L, Ismail S, Aglan MS, Zaki MS. 2013. Further delineation of the clinical spectrum in RNU4ATAC related microcephalic osteodysplastic primordial dwarfism type I. Am J Med Genet 161A:1875–1881. Edery P, Marcaillou C, Sahbatou M, Labalme A, Chastang J, Touraine R, Tubacher E, Senni F, Bober MB, Nampoothiri S, Jouk PS, Steichen E, Berland S, Toutain A, Wise CA, Sanlaville D, Rousseau F, ClergetDarpoux F, Leutenegger AL. 2011. Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA. Science 332:240–243. He H, Liyanarachchi S, Akagi K, Nagy R, Li J, Dietrich RC, Li W, Sebastian N, Wen B, Xin B, Singh J, Yan P, Alder H, Haan E, Wieczorek D, Albrecht B, Puffenberger E, Wang H, Westman JA, Padgett RA, Symer DE, de la Chapelle A. 2011. Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science 332:238–240.
921 Majewski F, Stoeckenius M, Kemperdick H. 1982. Studies of microcephalic primordial dwarfism III: An intrauterine dwarf with platyspondyly and anomalies of pelvis and clavicles-osteodysplastic primordial dwarfism type III. Am J Med Genet 12:37–42. Meinecke P, Passarge E. 1991. Microcephalic osteodysplastic primordial dwarfism type I/III in sibs. J Med G 28:795–800. Nagy R, Wang H, Albrecht B, Wieczorek D, Gillessen-Kaesbach G, Haan E, Meinecke P, Haan E, de la Chapelle A, Westman JA. 2012. Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the RNU4ATAC gene. Clin Genet 82: 140–146. Pierce MJ, Morse RP. 2012. The neurologic findings in Taybi-Linder syndrome (MOPD I/III): Case report and review of the literature. Am J Med Genet 158A:606–610. Taybi H, Linder D. 1967. Congenital familial dwarfism with cephalo skeletal dwarfism. Radiology 89:275–281. Taybi H. 1992. Letter to the Editor. Microcephalic osteodysplastic primordial dwarfism and cephalo-skeletal dysplasia (Taybi-Linder syndrome). Am J Med Genet 43:628–629. Vichi GF, Currarino G, Wasserman RL, Duvina PL, Filippi L. 2000. Cephaloskeletal dysplasia (Taybi-Linder syndrome: Osteodysplastic primordial dwarfism type III): Report of two cases and review of the literature. Pediatr Radiol 30:644–652. Winter RM, Wigglesworth J, Harding BN. 1985. Osteodysplastic primordial dwarfism: report of a further patient with manifestations similar to those seen in patients with types I and III. Am J Med Genet 21:569–574. Zuker M. 2003. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31:3406–3415.
SUPPORTING INFORMATION Additional supporting information may be found in the online version of this article at the publisher’s web-site.
A Novel Mutation in RNU4ATAC in a Patient with Microcephalic Osteodysplastic Primordial Dwarfism Type I Esra Kilic,1* Go¨khan Yigit,2,3,4 Gu¨len Eda Utine,1 Bernd Wollnik,2,3,4 Ercan Mihci,5 Banu Gu¨zel Nur,5 and Koray Boduroglu1 1
Faculty of Medicine, Division of Pediatric Genetics, Hacettepe University, Ankara, Turkey Institute of Human Genetics, University of Cologne, Cologne, Germany
2 3
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
4
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany Faculty of Medicine, Division of Pediatric Genetics, Akdeniz University, Antalya, Turkey
5
Manuscript Received: 3 July 2014; Manuscript Accepted: 21 December 2014
TO THE EDITOR: Microcephalic osteodysplastic primordial dwarfism type I (MOPD I; OMIM 210710), also named Taybi–Lindner syndrome, is a rare autosomal recessive disorder first described by Taybi and Linder [1967]. It is characterized by severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, bone dysplasia, brain malformations, hearing and vision impairment, and death occurs in infancy or early childhood. This disorder is distinguished from other microcephalic primordial dwarfism syndromes (e.g., MOPD II) by the presence of severe brain malformations, hyperkeratotic skin, and visual and hearing impairment [Winter et al., 1985; Meinecke and Passarge, 1991; Taybi, 1992]. In 2011, two studies identified mutations in the RNU4ATAC gene causing MOPD I [Edery et al., 2011; He et al., 2011]. RNU4ATAC (NG_029832.1) encodes a small nuclear RNA, U4atac, which is a crucial component of the minor U12-dependent spliceosome, and mutations in U4atac lead to decreased activity of the minor spliceosome, which is essential for splicing of about 800 U12type introns of genes of the human genome. Genes containing U12-type introns are involved in a broad variety of cellular processes including DNA replication and repair, RNA processing, and cytoskeletal organization, and defects in U12-dependent splicing can disrupt global cellular functions like proliferation, differentiation and cell growth [Edery et al., 2011; He et al., 2011]. To date, nine distinct mutations in RNU4ATAC among 40 patients with MOPD I have been described [Abdel-Salam et al., 2013]. Here we have identified a novel homozygous mutation in RNU4ATAC in a patient presenting with common features of MOPD I and, additionally, we document the rare phenotypic spectrum of MOPD I. The index patient, a 10-month-old boy on admission, was born as the second child to healthy first-degree cousins. His sister was healthy and there was no family history of any other genetic disease. He was born at 37th weeks of gestation by spontaneous vaginal delivery. During pregnancy, intrauterine growth retardation after the 20th week of gestation and pregnancy-induced hypertension
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Kilic E, Yigit G, Utine GE, Wollnik B, Mihci E, Nur BG, Boduroglu K. 2015. A novel mutation in RNU4ATAC In a patient with microcephalic osteodysplastic primordial dwarfism type I. Am J Med Genet Part A 167A:919–921.
were recorded. Amniocentesis showed a normal, 46,XY karyotype. Birth weight was 1335 g, length and OFC were not recorded. After birth, he had an infected urachal cyst excision. When he was clinically investigated at 10 months of age his weight was 4100 g (5.5 SD), length was 51 cm (7.3 SD) and OFC was 33 cm (10 SD). He had dry, hyperkeratotic skin diagnosed as lamellar ichthyosis, prominent metopic ridge, prominent eyes, sparse frontal scalp hair and eyebrows, a prominent nose with a bulbous tip, anteverted nares, long philtrum, thickened upper lip, mild retrognathia, and small ear lobules. Furthermore, he presented with short limbs, spade-like short hands with tapering fingers, edema and loose skin on hands, short feet with dorsal lymphedema, joint contracture on knees, short toes, small phallus with bilateral Funding/Conflict of interest: The authors declared no potential conflicts of interest. Our institutions consider this study in the realm of routine clinical care. Correspondence to: Esra Kilic, MD, Department of Pediatrics, Division of Pediatric Genetics, Hacettepe Univercity Ihsan Dog˘ramaci Children Hospital, Sihhiye, 06100, Ankara / Turkey. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 3 March 2015 DOI 10.1002/ajmg.a.36955
919
920 cryptorchidism, and a small scrotum (Supplemental Online Fig. 1). Neurological examination showed hypotonia with brisk reflexes. He was unable to control his head, had poor visual function and was not able to track his mother. During physical examination he showed only minimal interaction with environment, and his high squeaky nasal voice was remarkable. Ophthalmologic examination showed bilateral dense cataracts. Hearing tests showed bilateral sensorineural deficits. Abdominal and renal ultrasonography were normal. Echocardiography showed a small atrial septal defect. Skeletal radiologic examination showed small skull, short long bones, metaphyseal flaring, thin ribs, short metacarpals, small terminal phalanges, small iliac wings, horizontal acetabular fossae, absent ossification centers of the humeral heads and carpals (Supplemental Online Fig. 2). Magnetic resonance imaging (MRI) of the brain showed small frontal and parietal lobes, increased cerebrospinal fluid, simplified gyral pattern, small of the corpus callosum involving mainly the body and the splenium, and a small vermis (Supplemental Online Fig. 3). Routine laboratory tests including thyroid function tests and metabolic tests were normal, serological tests for intrauterine infections were negative. Chromosomal breakage studies utilizing diepoxybutane were normal. Within the first 12 months of age he had two episodes of pneumonia, and at 16 and 18 months of age, he had two episodes of bloody diarrhea. During these, he was febrile (39.5˚C–40˚C), had vomiting and mild hepatic failure with elevated liver enzymes. Due to recurrent infections, immunologic testing was performed showing moderate to significant reduction of total Immunoglobulin G level (387 mg/dl). Therefore, regular intravenous immunoglobulin therapy was started. At 19 months of age his weight was 4,800 g (4.6 SD), length was 57 cm (6.5 SD), and OFC was 34.5 cm (9.7 SD). He presented with a high, squeaky, nasal voice and frequent smiling. Despite hydration therapy, he still had dry, scaling skin. At 20 months of age he had a cataract operation following which he started to track his mother and to reach objects. At the most recent evaluation, he was 3 years old. Although he still showed marked developmental delay with poor head control and inability to sit without support, he was currently a sociable baby with frequent smiling. The diagnosis of MOPD I was made at 10 months of age based on clinical and skeletal findings in the patient. Genomic DNA of both parents and the index patient was screened for mutations in RNU4ATAC and Sanger-sequencing showed a novel, homozygous variant, g.46G>A, in the index patient. This variant was not annotated in dbSNP139 or the 1,000 Genomes Database, and both parents were heterozygous carrier for this alteration in RNU4ATAC (Supplemental Online Fig. 4). To date, only 40 patients with MOPD I with nine distinct mutations in RNU4ATAC have been described [Abdel-Salam et al., 2013]. This is a rare developmental disorder belonging to the spectrum of microcephalic primordial dwarfism (MPD) syndromes. Whereas all types of MPD show severe pre- and postnatal growth retardation, marked microcephaly and bone dysplasia, MOPD I is distinguished from other MPD syndromes based on severe brain anomalies and dry skin observed in affected patients [Majewski et al., 1982]. Furthermore, patients with MOPD I show a more severe global developmental delay and have a reduced life expectancy compared to other forms MPD, which lies in average around 8.5 months [Abdel-Salam et al., 2013]. The patient described
AMERICAN JOURNAL OF MEDICAL GENETICS PART A here showed all major findings of MOPD I (Supplemental Online Fig. 1). However, we did not observe seizures, kidney abnormalities, abnormal pigmentation or vasculopathy, which have been reported in MOPD I [Abdel-Salam et al., 2011; Pierce and Morse, 2012; Abdel-Salam et al., 2013]. Interestingly, the current patient presented with cataracts, which have only been reported once [Vichi et al., 2000], and hypogammaglobulinemia that, so far, was not observed in patients with MOPD I. Since it is reported that nearly half of the patients with MOPD I die due to infectious diseases [Abdel-Salam et al., 2013], the decreased serum immunglobulin G levels provide a possible explanation for the observed susceptibility to infections. Therefore, immunological profile should be considered when evaluating patients with MOPD I. The skeletal findings of the current patient are very similar to previously reported MOPD I patients. Radiological examination at the age of 10 months showed ridged metopic suture, short thinned cortex of long bones with metaphyseal broadening, delayed epiphyseal ossifications and hypoplastic phalanges. Further, the pelvis showed hypoplastic pubic bones and horizontal acetabular roofs (Supplemental Online Fig. 2). Cranial MRI of MOPD I patients show severe developmental brain malformations such as lissencephaly, poorly developed gyral pattern, malformed cerebrum with frontal pachygyria, enlarged ventricles, under myelinized white matter, thin corpus callosum and atrophic cerebellum [Pierce and Morse, 2012]. As a cardinal manifestation, almost all patients with MOPD I have partial or complete absence of the corpus callosum and 30% of reported patients have a small cerebellar vermis [Abdel-Salam et al., 2013]. Additionally, neuronal migration disorders are observed including pachygyria, lissencephaly, schisencephaly and polymicrogyria [Nagy et al., 2012]. At the age of 6 months, cranial MRI of the present patient showed small frontal lobes, simplified gyral pattern, small corpus callosum and vermis (Supplemental Online Fig. 3). To date, nine different mutations have been identified in the RNU4ATAC gene in patients with MOPD I, six of them, g.30G>A, g.50G>A, g.50G>C, g.51G>A, g.53C>G, g.55G>A, within the 50 stem loop and three of them, g.66G>C, g.111G>A, g.124G>A, located in the 30 stem loop of U4atac [Edery et al., 2011; He et al., 2011; Abdel-Salam et al., 2013]. Among these, the g.51G>A mutation is most frequently detected in patients with MOPD I. Although there is no obvious genotype-phenotype correlation, biallelic g.51G>A mutations have been associated with a shorter lifespan compared to other described mutations in RNU4ATAC [Nagy et al., 2012]. Compared to other primordial dwarfism syndromes, the prognosis of MOPD I is poor. The average life expectancy lies around 8.5 months, ranging from 2.5 to 18 months. Early death generally occurs within the first year of life and is mainly caused by infectious diseases. Up to date, the oldest patient reported died at 12.5 years of age due to pneumonia [Nagy et al., 2012]. The patient presented here in this study was 10 months of age when he was clinically evaluated, and is currently 3 years of age suggesting the possibility that the g.46G>A mutation might to be associated with longer survival. However, this conclusion is still preliminary and further patients with a similar mutation can confirm our assumption. The g.46G>A mutation lies within the 50 stem loop expanding the mutation spectrum in U4atac and underlining the importance of this structure for the function of U4atac. In silico modeling of U4atac structure using mfold predicts that the g.46G>A mutation
KILIC ET AL. drastically disrupts the 50 stem loop, which in wt U4atac is formed based on intramolecular base pairing within the U4atac snRNA (Supplemental Online Fig. 4B–C) [Zuker, 2003]. In conclusion, we report a newly described MOPD I patient carrying a novel mutation, g.46G>A, in RNU4ATAC. Presenting this additional patient and its phenotypic features may not only give a better understanding of the phenotypic variability within this disease, it will also provide further information for establishing a genotype-phenotype correlation in this rare disease and facilitate provision of accurate recurrence risks to families.
REFERENCES Abdel-Salam GM, Miyake N, Eid MM, Abdel-Hamid MS, Hassan NA, Eid OM, Effat LK, El-Badry TH, El-Kamah GY, El-Darouti M, Matsumoto N. 2011. A homozygous mutation in RNU4ATAC as a cause of microcephalic osteodysplastic primordial dwarfism type I (MOPD I) with associated pigmentary disorder. Am J Med Genet 155A:2885–2896. Abdel-Salam GM, Abdel-Hamid MS, Hassan NA, Issa MY, Effat L, Ismail S, Aglan MS, Zaki MS. 2013. Further delineation of the clinical spectrum in RNU4ATAC related microcephalic osteodysplastic primordial dwarfism type I. Am J Med Genet 161A:1875–1881. Edery P, Marcaillou C, Sahbatou M, Labalme A, Chastang J, Touraine R, Tubacher E, Senni F, Bober MB, Nampoothiri S, Jouk PS, Steichen E, Berland S, Toutain A, Wise CA, Sanlaville D, Rousseau F, ClergetDarpoux F, Leutenegger AL. 2011. Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA. Science 332:240–243. He H, Liyanarachchi S, Akagi K, Nagy R, Li J, Dietrich RC, Li W, Sebastian N, Wen B, Xin B, Singh J, Yan P, Alder H, Haan E, Wieczorek D, Albrecht B, Puffenberger E, Wang H, Westman JA, Padgett RA, Symer DE, de la Chapelle A. 2011. Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science 332:238–240.
921 Majewski F, Stoeckenius M, Kemperdick H. 1982. Studies of microcephalic primordial dwarfism III: An intrauterine dwarf with platyspondyly and anomalies of pelvis and clavicles-osteodysplastic primordial dwarfism type III. Am J Med Genet 12:37–42. Meinecke P, Passarge E. 1991. Microcephalic osteodysplastic primordial dwarfism type I/III in sibs. J Med G 28:795–800. Nagy R, Wang H, Albrecht B, Wieczorek D, Gillessen-Kaesbach G, Haan E, Meinecke P, Haan E, de la Chapelle A, Westman JA. 2012. Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the RNU4ATAC gene. Clin Genet 82: 140–146. Pierce MJ, Morse RP. 2012. The neurologic findings in Taybi-Linder syndrome (MOPD I/III): Case report and review of the literature. Am J Med Genet 158A:606–610. Taybi H, Linder D. 1967. Congenital familial dwarfism with cephalo skeletal dwarfism. Radiology 89:275–281. Taybi H. 1992. Letter to the Editor. Microcephalic osteodysplastic primordial dwarfism and cephalo-skeletal dysplasia (Taybi-Linder syndrome). Am J Med Genet 43:628–629. Vichi GF, Currarino G, Wasserman RL, Duvina PL, Filippi L. 2000. Cephaloskeletal dysplasia (Taybi-Linder syndrome: Osteodysplastic primordial dwarfism type III): Report of two cases and review of the literature. Pediatr Radiol 30:644–652. Winter RM, Wigglesworth J, Harding BN. 1985. Osteodysplastic primordial dwarfism: report of a further patient with manifestations similar to those seen in patients with types I and III. Am J Med Genet 21:569–574. Zuker M. 2003. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31:3406–3415.
SUPPORTING INFORMATION Additional supporting information may be found in the online version of this article at the publisher’s web-site.
