CLINICAL REPORT
A De Novo Mutation in KMT2A (MLL) in Monozygotic Twins with Wiedemann–Steiner Syndrome Sophie Dunkerton,1 Matthew Field,2 Vicki Cho,2 Edward Bertram,3 Belinda Whittle,3 Alexandra Groves,4 and Himanshu Goel1,4* 1
University of Newcastle, Callaghan, New South Wales, Australia Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra City, Australian Capital Territory, Australia 2
3
Australian Phenomics Facility, The Australian National University, Canberra City, Australian Capital Territory, Australia Hunter Genetics, Waratah, New South Wales, Australia
4
Manuscript Received: 17 December 2014; Manuscript Accepted: 9 April 2015
Growth deficiency, psychomotor delay, and facial dysmorphism was originally described in a male patient in 1989 by Wiedemann et al. and later in 2000 by Steiner et al. Wiedemann–Steiner syndrome (WSS) has since been described only a few times in the literature, with the phenotypic spectrum both expanding and becoming more delineated with each patient reported. We report on the clinical and molecular features of monozygotic twins with a de novo mutation in KMT2A. Single nucleotide polymorphism (SNP) microarray was done on both twins and whole-exome sequencing was done using both parents and one of the affected twins. SNP microarray confirmed that they were monozygotic twins. A de novo heterozygous variant (p. Arg1083*) in the KMT2A gene was identified through whole-exome sequencing, confirming the diagnosis of WSS. In this study, we have identified a de novo mutation in KMT2A associated with psychomotor developmental delay, facial dysmorphism, short stature, hypertrichosis cubiti, and small kidneys. This finding in monozygotic twins gives specificity to the WSS. The description of more cases of WSS is needed for further delineation of this condition. Small kidneys with normal function have not been described in this condition in the medical literature before. Ó 2015 Wiley Periodicals, Inc.
Key words: Wiedemann–Steiner syndrome; KMT2A; MLL; de novo; SNP; monozygotic twins; hypertrichosis cubiti
INTRODUCTION The combination of growth deficiency, a round flat face, psychomotor delay, hypertelorism, a long philtrum with low-set ears, short palpebral fissures, and a high palate was first described in a male patient in 1989 by Wiedemann et al. [1989]. They suggested that
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Dunkerton S, Field M, Cho V, Bertram E, Whittle B, Groves A, Goel H. 2015. A de novo Mutation in KMT2A (MLL) in monozygotic twins with Wiedemann– Steiner Syndrome. Am J Med Genet Part A 167A:2182–2187.
these features may represent a new syndrome. In Brazil, in 2000, Steiner and Marques reported another case of growth deficiency, unusual facies, and cognitive delay [Steiner and Marques, 2000]. The feature of hypertrichosis was described as being a potential addition to the syndrome and Wiedemann–Steiner syndrome (WSS) was reported as an entity [Steiner and Marques, 2000]. Since these studies, WSS has been described in a further 11 patients [Koenig et al., 2010; Jones et al., 2012; Mendelsohn et al., 2014; Strom et al., 2014], each time with new phenotypic features. Mutations in the KMT2A gene, formerly known as the mixedlineage leukemia gene (MLL) gene, have only recently been reported as being responsible for WSS [Jones et al., 2012]. Since then, the phenotype of this syndrome continues to expand as further cases are described. We describe here a pair of monozygotic twin sisters with WSS in whom molecular diagnosis was made after a whole-exome sequencing process. Conflict of interest: none Correspondence to: Himanshu Goel, Clinical Geneticist, PO Box 84, Waratah, NSW 2298, Australia. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 30 April 2015 DOI 10.1002/ajmg.a.37130
2182
DUNKERTON ET AL.
2183
CLINICAL REPORT
fissures, a wide and depressed nasal bridge, upturned nostrils, thick eyebrows and hair, long thick eyelashes, synophrys, thin vermilion of the lips, open mouth appearance, and excessive hair around elbows. She also had frontal upsweep, microretrognathia, narrow high arched palate and small hands and feet, and brisk deep tendon reflexes. (Fig. 1A and B) Overall, both twins looked identical in their facial appearance. They were enrolled in a mainstream public school with additional support and special education. Progress and learning are reported as slow but steadily improving. (Fig. 1A and B) Both twins had normal skeletal surveys and bone age. TSH and growth hormone study, liver function tests, renal function tests, complete blood count, lactate and venous blood gas analysis were also normal.
Monozygotic twin sisters were the only children of a Caucasian nonconsanguineous couple. Their mother had diet controlled gestational diabetes. Antenatal ultrasounds and fetal movements were normal. An emergency lower segment cesarean was done at 36 weeks of gestation for fetal bradycardia. There was no reported history of learning problems in family. Their father’s height was 164 cm (3–10th centile) and their mother’s height was 160.1–cm (25–50th centile). Midparental height was 155.5–cm (10th centile; 95%CI 149.5–161.5c m).
Twin 1 Twin 1 had birth weight of 1,932 gm (T De novo nonsense mutation 4 Premature termination
Twin 1
þ Small kidneys
þ þ
þ þ þ
þ þ þ þ þ
þ
þ
þ ? þ
c. 3247C>T De novo nonsense mutation 4 Premature termination
Twin 2
Present paper
DUNKERTON ET AL. 2185
2186 within exon 4 of the KMT2A gene on chromosome 11 at 118347610bp, resulting in a premature termination of the 36 exon protein with a strong likelihood of a functional impact due to the absence of key domains. This variant was validated by a fluorescent KASP assay (LGCgenomics, Teddington, Middlesex, UK) and confirmed to be present in affected both twins and absent in the parental DNA. This variant was absent in 1000 Genomes Project data (n ¼ 1700) and the Exome Variant Server (EVS) data that cover 6,500 individuals of European-American and African-American origin.
DISCUSSION Monozygotic twinning in humans is due to the splitting of a single zygote; however, the cause is still largely unknown. They share identical genomes, and therefore generally identical phenotypes. Here, we report on the first case of monozygotic twins with WSS. The twins described in this report had whole-exome sequencing involving trio of parents and an affected child. A de novo novel variant in KMT2A gene was identified and lead to the molecular diagnosis of WSS. In 2010, the phenotype of WSS was expanded by Koenig et al. [2010] who described a further three cases following the phenotype originally reported by Wiedemann in 1989 and Steiner in 2000 [Wiedemann, 1989; Steiner and Marques, 2000]. These three cases added the facial features of thick eyebrows, a broad, thick nasal tip, long philtrum, thin upper lip, and prominent long chin. In Weidemann’s report, the father of the child was described as having similar facial features [Wiedemann, 1989], whereas in Koenig et al. [2010], all three cases appeared to be sporadic. Koenig et al. also suggested the facial gestalt became more pronounced with age, making it easier to diagnose as the child becomes older and in our case, the diagnosis was not confirmed until the age of 10 years. In 2012, Jones et al. [2012] identified mutations in KMT2A gene in five out of six children with clinical diagnosis of WSS and demonstrated it as an autosomal dominant disorder. Later Strom et al. [2014] described two unrelated children (both with Mexican heritage) with de novo DNA variants in the KMT2A gene. Hypertrichosis cubiti (“hairy elbow”) is a well-recognized but under-reported entity [Martinez de Lagran et al., 2010]. This may be associated with genetic syndrome like WSS or nonspecific systems involvement. WSS was defined as the presence of hypertrichosis cubiti with variable additional features [Flannery et al., 1989; MacDermot et al., 1989]. As Martinez de Lagran et al. [2010] highlighted, the phenotypic spectrum of WSS may, therefore, be much broader if hypertrichosis cubiti is not a universal finding. Both twins reported here had the hypertrichosis cubiti. This article further expands the spectrum of clinical phenotypes. In this report, both twins exhibited the facial dysmorphism of hypertelorism, small palpebral fissures, synophrys, small hands and feet, short stature, and hypertrichosis. Advanced bone age has also been described as a feature of WSS [Koenig et al., 2010; Mendelsohn et al., 2014]; however, our patients had normal bone age. Features not previously described in the literature include patent ductus arteriosus and small kidneys with normal renal function. Internal organ involvement in WSS has been described twice; in Mendelsohn et al., with vesicoureteral reflux and a unilateral ure-
AMERICAN JOURNAL OF MEDICAL GENETICS PART A tocele, and also in Wiedemann’s original article where a wide renal calyces was described [Wiedemann, 1989; Mendelsohn et al., 2014]. The fact that monozygotic twins exhibited this renal manifestation strengthens its association with the mutation in KLMT2A. The small kidneys were associated with normal function; however, as the patients are still young, this needs to have ongoing monitoring. Monozygotic twins with chromosomal abnormalities have been reported occasionally; however, single gene disorders presenting in monozygotic twins have been reported rarely. A case of male monozygotic twins with Beckworth–Wiedemann syndrome was reported in 2014 [Elalaoui et al., 2014]. However, only one twin was affected and the psychomotor development was normal. Few reports of intellectual disability and dysmorphic syndrome in monozygotic twins with genetic mutations have been described in the literature. Mutation-positive cases of WSS have been described after 2012 when the gene was identified. Previously only 10 patients with WSS have been described clinically. Mutations and phenotypic variations occur among cases (Table I). All five mutation-positive cases described by Jones et al. [2012] had mutations leading to premature termination of reading frame. Four out of five patients in that report had mutation in exon 27 and one patient had in exon 13. There is some evidence that a stop codon mutation is responsible for causing the symptoms; however, Strom et al. [2014] described missense mutation in exon 13 and a splice mutation in intron 8 in one patient each. The mutations in KMT2A gene seem to be distributed through the length of the gene. The mutation in our patients was in exon 4 of KMT2A gene. With the small amount of literature available, we can only speculate the correlation between the genotype and phenotype in WSS. (Table I)
CONCLUSION This article describes the first reported case of monozygotic twins with a molecular diagnosis of WSS. It outlines the typical facial dysmorphism, growth deficiency, and psychomotor delay that are consistent with previous reported cases. Patent ductus arteriosis has also been described in one patient, and small kidneys with normal renal function in both twins. This case report not only expands the phenotypic spectrum that has already been described in the literature but may also add specificity to WSS as a clinical entity. There was also a limited attempt to find a genotype–phenotype correlation. The description of more cases of WSS is needed for understanding the complete phenotype of this condition.
ACKNOWLEDGMENTS The authors thank the patients’ family for giving permission to write this article.
REFERENCES Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. 2010. A method and server for predicting damaging missense mutations. Nat Methods 7:248–249. Elalaoui SC, Garin I, Sefiani A, Perez de Nanclares G. 2014. Maternal hypomethylation of KvDMR in a monozygotic male twin pair discordant for Beckwith-Wiedemann syndrome. Mol Syndromol 5:41–46.
DUNKERTON ET AL. Flannery DB, Fink SM, Francis G, Gilman PA. 1989. Hypertrichosis cubiti. Am J Med Genet 32:482–483. Jones WD, Dafou D, McEntagart M, Woollard WJ, Elmslie FV, HolderEspinasse M, Irving M, Saggar AK, Smithson S, Trembath RC, Deshpande C, Simpson MA. 2012. De novo mutations in MLL cause Wiedemann-Steiner syndrome. Am J Hum Genet 91:358–364. Koenig R, Meinecke P, Kuechler A, Schafer D, Muller D. 2010. Wiedemann-Steiner syndrome: Three further cases. Am J Med Genet Part A 152A:2372–2375. Kumar P, Henikoff S, Ng PC. 2009. Predicting the effects of coding nonsynonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081. Li H, Durbin R. 2009. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R. Genome Project Data Processing S. 2009. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25:2078–2079. MacDermot KD, Patton MA, Williams MJ, Winter RM. 1989. Hypertrichosis cubiti (hairy elbows) and short stature: A recognisable association. J Med Genet 26:382–385.
2187 Martinez de Lagran Z, Gonzalez-Perez R, Asuncion Arregui-Murua M, Soloeta-Arechavala R. 2010. Hypertrichosis cubiti: Another case of a wellrecognized but under-reported entity. Pediatr Dermatol 27:310–311. Mendelsohn BA, Pronold M, Long R, Smaoui N, Slavotinek AM. 2014. Advanced bone age in a girl with Wiedemann-Steiner syndrome and an exonic deletion in KMT2A (MLL). Am J Med Genet Part A 164A:2079– 2083. Steiner CE, Marques AP. 2000. Growth deficiency, mental retardation and unusual facies. Clin Dysmorphol 9:155–156. Strom SP, Lozano R, Lee H, Dorrani N, Mann J, O’Lague PF, Mans N, Deignan JL, Vilain E, Nelson SF, Grody WW, Quintero-Rivera F. 2014. De novo variants in the KMT2A (MLL) gene causing atypical Wiedemann-Steiner syndrome in two unrelated individuals identified by clinical exome sequencing. BMC Med Genet 15:49. Wang K, Li M, Hakonarson H. 2010. ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164. Wiedemann HR, Grosse F-R, Dibbern H. 1989. A syndrome of abnormal facies, short stature, and psychomotor retardation. Atlas of clinician syndromes: A visual aid to diagnosis for clinicians and practicing physicians, 2nd edition. pp 198–199.
A De Novo Mutation in KMT2A (MLL) in Monozygotic Twins with Wiedemann–Steiner Syndrome Sophie Dunkerton,1 Matthew Field,2 Vicki Cho,2 Edward Bertram,3 Belinda Whittle,3 Alexandra Groves,4 and Himanshu Goel1,4* 1
University of Newcastle, Callaghan, New South Wales, Australia Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra City, Australian Capital Territory, Australia 2
3
Australian Phenomics Facility, The Australian National University, Canberra City, Australian Capital Territory, Australia Hunter Genetics, Waratah, New South Wales, Australia
4
Manuscript Received: 17 December 2014; Manuscript Accepted: 9 April 2015
Growth deficiency, psychomotor delay, and facial dysmorphism was originally described in a male patient in 1989 by Wiedemann et al. and later in 2000 by Steiner et al. Wiedemann–Steiner syndrome (WSS) has since been described only a few times in the literature, with the phenotypic spectrum both expanding and becoming more delineated with each patient reported. We report on the clinical and molecular features of monozygotic twins with a de novo mutation in KMT2A. Single nucleotide polymorphism (SNP) microarray was done on both twins and whole-exome sequencing was done using both parents and one of the affected twins. SNP microarray confirmed that they were monozygotic twins. A de novo heterozygous variant (p. Arg1083*) in the KMT2A gene was identified through whole-exome sequencing, confirming the diagnosis of WSS. In this study, we have identified a de novo mutation in KMT2A associated with psychomotor developmental delay, facial dysmorphism, short stature, hypertrichosis cubiti, and small kidneys. This finding in monozygotic twins gives specificity to the WSS. The description of more cases of WSS is needed for further delineation of this condition. Small kidneys with normal function have not been described in this condition in the medical literature before. Ó 2015 Wiley Periodicals, Inc.
Key words: Wiedemann–Steiner syndrome; KMT2A; MLL; de novo; SNP; monozygotic twins; hypertrichosis cubiti
INTRODUCTION The combination of growth deficiency, a round flat face, psychomotor delay, hypertelorism, a long philtrum with low-set ears, short palpebral fissures, and a high palate was first described in a male patient in 1989 by Wiedemann et al. [1989]. They suggested that
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Dunkerton S, Field M, Cho V, Bertram E, Whittle B, Groves A, Goel H. 2015. A de novo Mutation in KMT2A (MLL) in monozygotic twins with Wiedemann– Steiner Syndrome. Am J Med Genet Part A 167A:2182–2187.
these features may represent a new syndrome. In Brazil, in 2000, Steiner and Marques reported another case of growth deficiency, unusual facies, and cognitive delay [Steiner and Marques, 2000]. The feature of hypertrichosis was described as being a potential addition to the syndrome and Wiedemann–Steiner syndrome (WSS) was reported as an entity [Steiner and Marques, 2000]. Since these studies, WSS has been described in a further 11 patients [Koenig et al., 2010; Jones et al., 2012; Mendelsohn et al., 2014; Strom et al., 2014], each time with new phenotypic features. Mutations in the KMT2A gene, formerly known as the mixedlineage leukemia gene (MLL) gene, have only recently been reported as being responsible for WSS [Jones et al., 2012]. Since then, the phenotype of this syndrome continues to expand as further cases are described. We describe here a pair of monozygotic twin sisters with WSS in whom molecular diagnosis was made after a whole-exome sequencing process. Conflict of interest: none Correspondence to: Himanshu Goel, Clinical Geneticist, PO Box 84, Waratah, NSW 2298, Australia. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 30 April 2015 DOI 10.1002/ajmg.a.37130
2182
DUNKERTON ET AL.
2183
CLINICAL REPORT
fissures, a wide and depressed nasal bridge, upturned nostrils, thick eyebrows and hair, long thick eyelashes, synophrys, thin vermilion of the lips, open mouth appearance, and excessive hair around elbows. She also had frontal upsweep, microretrognathia, narrow high arched palate and small hands and feet, and brisk deep tendon reflexes. (Fig. 1A and B) Overall, both twins looked identical in their facial appearance. They were enrolled in a mainstream public school with additional support and special education. Progress and learning are reported as slow but steadily improving. (Fig. 1A and B) Both twins had normal skeletal surveys and bone age. TSH and growth hormone study, liver function tests, renal function tests, complete blood count, lactate and venous blood gas analysis were also normal.
Monozygotic twin sisters were the only children of a Caucasian nonconsanguineous couple. Their mother had diet controlled gestational diabetes. Antenatal ultrasounds and fetal movements were normal. An emergency lower segment cesarean was done at 36 weeks of gestation for fetal bradycardia. There was no reported history of learning problems in family. Their father’s height was 164 cm (3–10th centile) and their mother’s height was 160.1–cm (25–50th centile). Midparental height was 155.5–cm (10th centile; 95%CI 149.5–161.5c m).
Twin 1 Twin 1 had birth weight of 1,932 gm (T De novo nonsense mutation 4 Premature termination
Twin 1
þ Small kidneys
þ þ
þ þ þ
þ þ þ þ þ
þ
þ
þ ? þ
c. 3247C>T De novo nonsense mutation 4 Premature termination
Twin 2
Present paper
DUNKERTON ET AL. 2185
2186 within exon 4 of the KMT2A gene on chromosome 11 at 118347610bp, resulting in a premature termination of the 36 exon protein with a strong likelihood of a functional impact due to the absence of key domains. This variant was validated by a fluorescent KASP assay (LGCgenomics, Teddington, Middlesex, UK) and confirmed to be present in affected both twins and absent in the parental DNA. This variant was absent in 1000 Genomes Project data (n ¼ 1700) and the Exome Variant Server (EVS) data that cover 6,500 individuals of European-American and African-American origin.
DISCUSSION Monozygotic twinning in humans is due to the splitting of a single zygote; however, the cause is still largely unknown. They share identical genomes, and therefore generally identical phenotypes. Here, we report on the first case of monozygotic twins with WSS. The twins described in this report had whole-exome sequencing involving trio of parents and an affected child. A de novo novel variant in KMT2A gene was identified and lead to the molecular diagnosis of WSS. In 2010, the phenotype of WSS was expanded by Koenig et al. [2010] who described a further three cases following the phenotype originally reported by Wiedemann in 1989 and Steiner in 2000 [Wiedemann, 1989; Steiner and Marques, 2000]. These three cases added the facial features of thick eyebrows, a broad, thick nasal tip, long philtrum, thin upper lip, and prominent long chin. In Weidemann’s report, the father of the child was described as having similar facial features [Wiedemann, 1989], whereas in Koenig et al. [2010], all three cases appeared to be sporadic. Koenig et al. also suggested the facial gestalt became more pronounced with age, making it easier to diagnose as the child becomes older and in our case, the diagnosis was not confirmed until the age of 10 years. In 2012, Jones et al. [2012] identified mutations in KMT2A gene in five out of six children with clinical diagnosis of WSS and demonstrated it as an autosomal dominant disorder. Later Strom et al. [2014] described two unrelated children (both with Mexican heritage) with de novo DNA variants in the KMT2A gene. Hypertrichosis cubiti (“hairy elbow”) is a well-recognized but under-reported entity [Martinez de Lagran et al., 2010]. This may be associated with genetic syndrome like WSS or nonspecific systems involvement. WSS was defined as the presence of hypertrichosis cubiti with variable additional features [Flannery et al., 1989; MacDermot et al., 1989]. As Martinez de Lagran et al. [2010] highlighted, the phenotypic spectrum of WSS may, therefore, be much broader if hypertrichosis cubiti is not a universal finding. Both twins reported here had the hypertrichosis cubiti. This article further expands the spectrum of clinical phenotypes. In this report, both twins exhibited the facial dysmorphism of hypertelorism, small palpebral fissures, synophrys, small hands and feet, short stature, and hypertrichosis. Advanced bone age has also been described as a feature of WSS [Koenig et al., 2010; Mendelsohn et al., 2014]; however, our patients had normal bone age. Features not previously described in the literature include patent ductus arteriosus and small kidneys with normal renal function. Internal organ involvement in WSS has been described twice; in Mendelsohn et al., with vesicoureteral reflux and a unilateral ure-
AMERICAN JOURNAL OF MEDICAL GENETICS PART A tocele, and also in Wiedemann’s original article where a wide renal calyces was described [Wiedemann, 1989; Mendelsohn et al., 2014]. The fact that monozygotic twins exhibited this renal manifestation strengthens its association with the mutation in KLMT2A. The small kidneys were associated with normal function; however, as the patients are still young, this needs to have ongoing monitoring. Monozygotic twins with chromosomal abnormalities have been reported occasionally; however, single gene disorders presenting in monozygotic twins have been reported rarely. A case of male monozygotic twins with Beckworth–Wiedemann syndrome was reported in 2014 [Elalaoui et al., 2014]. However, only one twin was affected and the psychomotor development was normal. Few reports of intellectual disability and dysmorphic syndrome in monozygotic twins with genetic mutations have been described in the literature. Mutation-positive cases of WSS have been described after 2012 when the gene was identified. Previously only 10 patients with WSS have been described clinically. Mutations and phenotypic variations occur among cases (Table I). All five mutation-positive cases described by Jones et al. [2012] had mutations leading to premature termination of reading frame. Four out of five patients in that report had mutation in exon 27 and one patient had in exon 13. There is some evidence that a stop codon mutation is responsible for causing the symptoms; however, Strom et al. [2014] described missense mutation in exon 13 and a splice mutation in intron 8 in one patient each. The mutations in KMT2A gene seem to be distributed through the length of the gene. The mutation in our patients was in exon 4 of KMT2A gene. With the small amount of literature available, we can only speculate the correlation between the genotype and phenotype in WSS. (Table I)
CONCLUSION This article describes the first reported case of monozygotic twins with a molecular diagnosis of WSS. It outlines the typical facial dysmorphism, growth deficiency, and psychomotor delay that are consistent with previous reported cases. Patent ductus arteriosis has also been described in one patient, and small kidneys with normal renal function in both twins. This case report not only expands the phenotypic spectrum that has already been described in the literature but may also add specificity to WSS as a clinical entity. There was also a limited attempt to find a genotype–phenotype correlation. The description of more cases of WSS is needed for understanding the complete phenotype of this condition.
ACKNOWLEDGMENTS The authors thank the patients’ family for giving permission to write this article.
REFERENCES Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. 2010. A method and server for predicting damaging missense mutations. Nat Methods 7:248–249. Elalaoui SC, Garin I, Sefiani A, Perez de Nanclares G. 2014. Maternal hypomethylation of KvDMR in a monozygotic male twin pair discordant for Beckwith-Wiedemann syndrome. Mol Syndromol 5:41–46.
DUNKERTON ET AL. Flannery DB, Fink SM, Francis G, Gilman PA. 1989. Hypertrichosis cubiti. Am J Med Genet 32:482–483. Jones WD, Dafou D, McEntagart M, Woollard WJ, Elmslie FV, HolderEspinasse M, Irving M, Saggar AK, Smithson S, Trembath RC, Deshpande C, Simpson MA. 2012. De novo mutations in MLL cause Wiedemann-Steiner syndrome. Am J Hum Genet 91:358–364. Koenig R, Meinecke P, Kuechler A, Schafer D, Muller D. 2010. Wiedemann-Steiner syndrome: Three further cases. Am J Med Genet Part A 152A:2372–2375. Kumar P, Henikoff S, Ng PC. 2009. Predicting the effects of coding nonsynonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081. Li H, Durbin R. 2009. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R. Genome Project Data Processing S. 2009. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25:2078–2079. MacDermot KD, Patton MA, Williams MJ, Winter RM. 1989. Hypertrichosis cubiti (hairy elbows) and short stature: A recognisable association. J Med Genet 26:382–385.
2187 Martinez de Lagran Z, Gonzalez-Perez R, Asuncion Arregui-Murua M, Soloeta-Arechavala R. 2010. Hypertrichosis cubiti: Another case of a wellrecognized but under-reported entity. Pediatr Dermatol 27:310–311. Mendelsohn BA, Pronold M, Long R, Smaoui N, Slavotinek AM. 2014. Advanced bone age in a girl with Wiedemann-Steiner syndrome and an exonic deletion in KMT2A (MLL). Am J Med Genet Part A 164A:2079– 2083. Steiner CE, Marques AP. 2000. Growth deficiency, mental retardation and unusual facies. Clin Dysmorphol 9:155–156. Strom SP, Lozano R, Lee H, Dorrani N, Mann J, O’Lague PF, Mans N, Deignan JL, Vilain E, Nelson SF, Grody WW, Quintero-Rivera F. 2014. De novo variants in the KMT2A (MLL) gene causing atypical Wiedemann-Steiner syndrome in two unrelated individuals identified by clinical exome sequencing. BMC Med Genet 15:49. Wang K, Li M, Hakonarson H. 2010. ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164. Wiedemann HR, Grosse F-R, Dibbern H. 1989. A syndrome of abnormal facies, short stature, and psychomotor retardation. Atlas of clinician syndromes: A visual aid to diagnosis for clinicians and practicing physicians, 2nd edition. pp 198–199.
