RESEARCH LETTER
Refinement of the 8q22.1 Microdeletion Critical Region Associated With Nablus Mask-Like Facial Syndrome Justin Overhoff,1 Marina M. Rabideau,1 Lynne M. Bird,2 Daniela N. Schweitzer,3,4 Karla Haynes,4 Roger A. Schultz,1 Lisa G. Shaffer,1 Jill A. Rosenfeld,1* and Jay W. Ellison1 1
Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, Washington Department of Pediatrics, University of California San Diego and Rady Children’s Hospital, San Diego, California
2 3
Department of Medical Genetics, Children’s Hospital Los Angeles, Los Angeles, California
4
Craniofacial and Cleft Center, Children’s Hospital Los Angeles, Los Angeles, California
Manuscript Received: 21 June 2013; Manuscript Accepted: 14 July 2013
TO THE EDITOR: The characteristic phenotype of Nablus mask-like facial syndrome (NMLFS), first described by Teebi [2000], consists of tight, glistening facial skin, blepharophimosis, ocular hypertelorism, abnormal ear architecture, sparse eyebrows, and an upswept frontal hairline. Some patients with NMLFS exhibit other features, including microcephaly, cryptorchidism, cleft palate, friendly demeanor, and a spectrum of neurologic phenotypes ranging from normal to complex motor and speech delays [Shieh et al., 2006; Raas-Rothschild et al., 2009]. The first genetic abnormalities associated with NMLFS were reported by Shieh et al. [2006], who described two affected individuals with chromosomal microdeletions spanning 8q21.3q22.1 detected by array comparative genomic hybridization (aCGH). Two subsequent reports described three additional probands with NMLFS and 8q22.1 deletions [Barber et al., 2008; RaasRothschild et al., 2009]; the commonly deleted region in all five patients defined a critical region of 2.8 Mb that presumably contains the causative gene(s) for the disorder (Fig. 1). Here we describe two individuals with the typical NMLFS phenotype who carry novel 8q22.1 microdeletions. One deletion reduces the size of the critical region associated with NMLFS. Informed consent was obtained to publish clinical data and images. Patient 1 is a 12-year-old male who was born prematurely at 27 weeks gestation following a pregnancy reportedly complicated by prenatal maternal street drug exposure. He is adopted; the family history is unknown. He was born with the characteristic NMLFS dysmorphic features, including tight, glistening facial skin with dimpling, blepharophimosis, arched eyebrows, bi-temporal narrowing, and dysplastic ears. His ears were low-set, posteriorly angulated, and had a prominent superior helix, hypoplastic inferior helix, a Y-shaped antihelix with a short trunk to the Y, and hypoplastic lobules (Fig. 2A,B). He presented at birth with a forme fruste cleft lip and high palate. His growth parameters have been within normal limits since birth. The patient has undergone surgical repair of penile chordee, bilateral inguinal hernias, bilateral cryptorchidism, and bilateral strabismus. Brain MRI was normal, and he
Ó 2013 Wiley Periodicals, Inc.
How to Cite this Article: Overhoff J, Rabideau MM, Bird LM, Schweitzer DN, Haynes K, Schultz RA, Shaffer LG, Rosenfeld JA, Ellison JW. 2014. Refinement of the 8q22.1 microdeletion critical region associated with Nablus masklike facial syndrome. Am J Med Genet Part A 164A:259–263.
has average intelligence. At age 12 years he had attention deficithyperactivity and obsessive-compulsive symptoms, chronic mild constipation, delayed fine motor and motor oral skills, and toe walking due to tight Achilles tendons. Patient 2 is an 11-week-old male with multiple congenital abnormalities who was born at 37 weeks gestation to phenotypically normal parents of Chinese and Palauan ancestry. Severe micrognathia, a large U-shaped cleft palate, low-set dysplastic ears, anterior cervical pits symmetrically located lateral to the trachea just below the mandible and another more inferiorly located on the right side of the neck, and cryptorchidism were noted. At birth, the
Conflict of interest: Justin Overhoff, Roger A. Schultz, and Jill A. Rosenfeld are employees of Signature Genomic Laboratories, a subsidiary of PerkinElmer, Inc. All other authors have no conflicts to declare. Marina M. Rabideau’s present address is InVitae, San Francisco, CA Lisa G. Shaffer’s present address is Paw Print Genetics, Genetic Veterinary Sciences, Inc, Spokane, WA Correspondence to: Jill Rosenfeld, M.S., LCGC, Signature Genomic Laboratories, PerkinElmer, Inc., 2820 North Astor Street, Spokane, WA 99207. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 20 November 2013 DOI 10.1002/ajmg.a.36163
259
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
FIG. 1. Schematic showing deletions involving 8q22.1. A: Full idiogram of chromosome 8 is across the top, with a partial idiogram of chromosome bands 8q21.3q22.1 below (hg19). Pink bar and vertical gray-shaded region show the NMLFS critical region. Orange and purple bars represent cases with and without NMLFS, respectively. Horizontal black lines extend through gaps in coverage to show maximum deletion sizes. B: Zoomed-in region, showing patients in this report and the narrowed NMLFS critical deletion region (dashed lines). Blue bars represent genes in the region.
patient weighed 2,880 g (25th–50th centile) and attained Apgar scores of 4 and 7 at 1 and 5 min, respectively. He had a normal echocardiogram, and a renal ultrasound revealed echogenic kidneys. A CT scan showed prominent fluid collection in the posterior fossa, decreased attenuation in the subcortical and periventricular white matter, and bilateral frontoparietal polymicrogyria (Fig. 2E,
F). At 11 weeks, all growth parameters were within normal range, though relative microcephaly was present (OFC 37.2 cm, 10th centile; crown-rump length 38 cm). A large right inguinal hernia and hypoplastic distal interphalangeal creases with recessed first toes were noted. He was alert, interactive, and focused on faces. His dysmorphic features were characteristic of NMLFS, including
OVERHOFF ET AL.
Mild: 2/11 0/7 2/10 4/11 4/11 3/11 1/9 1/11 4/11 1/11 1/7 0/11 (Continued) 4/6 4/6 4/4 6/6 5/5 4/4 4/4 6/6 4/6 6/6 2/6 2/3 þ NS þ Laterally sparse þ þ þ þ U-shaped NA þ þ þ Arched þ ; forme fruste cleft lip þ þ ; horizontal chin dimple þ High palate
Individuals with 8q22.1 deletions and NMLFSa Male (4), Female (2) 9 months to adult Varies (Fig. 1) De novo (4), maternal (1) Patient 2 Male 11 weeks 94,433,633–97,127,724 Unknown
Sex Age at evaluation Deletion coordinates (chr8, hg19) Inheritance Dysmorphic features Tight glistening facial skin Upswept frontal hair pattern Hypertelorism or telecanthus Highly arched, sparse eyebrows Flat, bulbous nasal tip Long philtrum Cheek dimples Blepharophimosis Micrognathia Abnormal ear shape Cleft palate Abnormal dentition
blepharophimosis, prominent cheeks with tight facial skin, and dysplastic ears. His ears were low-set, posteriorly angulated, and had slit-like external auditory canals, a prominent superior helix, a hypoplastic inferior helix, and a V-shaped antihelix (Fig. 2C,D). Oligonucleotide-based aCGH was performed using customdesigned SignatureChipOS, version 1 (Patient 1; 105K-feature, manufactured by Agilent Technologies, Santa Clara, CA) and version 2 (Patient 2; 135K-feature, manufactured by Roche NimbleGen, Madison, WI), according to previously described methods [Ballif et al., 2008; Duker et al., 2010]. Patients 1 and 2 have overlapping deletions within 8q22.1, 3.5 and 2.7 Mb, respectively (Table I, Fig. 1). Neither patient had other significant copy
Patient 1 Male 12 years 93,417,059–96,901,832 Unknown
FIG. 2. Phenotypic features of Patients 1 and 2. A,B: Patient 1 at 8 years of age. C,D: Patient 2 at 11 weeks of age. Both subjects show typical NMLFS facial features, including tight, glistening facial skin, laterally sparse eyebrows, telecanthus, blepharophimosis, bulbous nasal tip, micrognathia, and abnormal ears. E,F: Brain imaging for Patient 2 showed prominent fluid in the posterior fossa, decreased attenuation in subcortical and periventricular white matter, and bilateral frontoparietal polymicrogyria.
TABLE I. Clinical Features of Individuals With 8q22.1 Deletions
Individuals with 8q22.1 deletions and without NMLFSb Male (6), Female (5) 6 months to adult Varies (Fig. 1) De novo (8), maternal (2)
261
Non-contributory Family history
ADHD, attention deficit hyperactivity disorder; CHD, congenital heart defect; DD, developmental delay; ID, intellectual disability; NA, not applicable; NS, not specified; þ, feature present; , feature absent. a Five probands and one mother previously reported [Shieh et al., 2006; Barber et al., 2008; Raas-Rothschild et al., 2009]. b Nine probands and two mothers previously reported [Jain et al., 2010; Allanson et al., 2012; Debost-Legrand et al., 2013].
2/11 3 with autistic features; 1 with ADHD; 4 with CHD þ Born at 27 weeks, prenatal drug exposure, ADHD Unknown Happy/friendly disposition Other features
Brain abnormalities Postnatal microcephaly Cryptorchidism Hypoplastic/abnormal genitalia Widely spaced nipples Contractures/camptodactyly
DD/ID
4/4
1/2 4/5 3/3 3/4 2/4 2/4
þ (Fig. 2) þ; inguinal hernia þ NS Hypoplastic interphalangeal creases, 1st toes recessed NA Echogenic kidneys, cervical pits
Individuals with 8q22.1 deletions and NMLFSa 5/6 (variable severity) Patient 2 NA
Patient 1 þ; motor delay, normal intelligence Normal MRI þ; bilateral inguinal hernias þ; chordee Tight heel cords
TABLE I. (Continued )
1/1 4/10 2/6 3/10 0/5 1/9 (clubfeet)
AMERICAN JOURNAL OF MEDICAL GENETICS PART A Individuals with 8q22.1 deletions and without NMLFSb 11/11 (variable severity)
262
number abnormalities. Patient 2’s deletion did not include the centromeric 1 Mb of the previously defined critical region, allowing a narrowing of the NMLFS critical region to 1.84 Mb, from 94.43 to 96.27 Mb (hg19; Fig. 1). There have been reports of patients with deletions of all or part of the critical NMLFS region without the Nablus phenotype, who were tested for other indications (Fig. 1, Table I) [Jain et al., 2010; Allanson et al., 2012; Debost-Legrand et al., 2013]. In the most recent report, the authors concluded that because their patient did not display the phenotype, the deleted region in their patient does not contain critical genes for the disorder, thus significantly reducing the size of the critical region [Debost-Legrand et al., 2013]. However, Allanson et al. [2012] recently presented nine patients with deletions in the region (including two mother–child pairs), none of whom displayed the characteristic phenotype of NMLFS. Five of these patients were deleted for the entire region implicated by the previous reports of affected individuals. The authors concluded that deletion of the 8q22.1 region is necessary, but not sufficient, for development of the NMFLS phenotype. Another way of restating the conclusion of Allanson et al. [2012] is that the penetrance of the phenotype is reduced when deletions are present in the region. Therefore, unaffected individuals cannot be used to define the critical region. Here we report two individuals penetrant for the NMLFS phenotype, one narrowing the critical region for the disorder. Our Patient 2 was not deleted for the centromeric 1 Mb of the previously defined critical region, thereby reducing the critical region. Three genes (FLJ46284, TRIQK, and C8orf87) deleted in all other affected individuals are intact in our Patient 2, making it less likely that haploinsufficiency of one or more of these genes leads to the phenotype (though cis position effects could still conceivably alter their expression). Identification of additional affected individuals with smaller deletions or point mutations are needed to provide further insights into the pathogenesis of this disorder.
ACKNOWLEDGMENTS We thank Erin Dodge (Signature Genomics) for assistance with figure creation.
REFERENCES Allanson J, Smith A, Hare H, Albrecht B, Bijlsma E, Dallapiccola B, Donti E, Fitzpatrick D, Isidor B, Lachlan K, Le Caignec C, Prontera P, Raas-Rothschild A, Rogaia D, van Bon B, Aradhya S, Crocker SF, Jarinova O, McGowan-Jordan J, Boycott K, Bulman D, Fagerberg CR. 2012. Nablus mask-like facial syndrome: Deletion of chromosome 8q22.1 is necessary but not sufficient to cause the phenotype. Am J Med Genet Part A 158A:2091–2099. Ballif BC, Theisen A, McDonald-McGinn DM, Zackai EH, Hersh JH, Bejjani BA, Shaffer LG. 2008. Identification of a previously unrecognized microdeletion syndrome of 16q11.2q12.2. Clin Genet 74:469–475. Barber JC, Maloney VK, Huang S, Bunyan DJ, Cresswell L, Kinning E, Benson A, Cheetham T, Wyllie J, Lynch SA, Zwolinski S, Prescott L, Crow Y, Morgan R, Hobson E. 2008. 8p23.1 duplication syndrome; a novel genomic condition with unexpected complexity revealed by array CGH. Eur J Hum Genet 16:18–27.
OVERHOFF ET AL.
263
Debost-Legrand A, Eymard-Pierre E, Pebrel-Richard C, Gouas L, Goumy C, Giollant M, Ayed W, Tchirkov A, Francannet C, Vago P. 2013. A new case of 8q22.1 microdeletion restricts the critical region for Nablus masklike facial syndrome. Am J Med Genet Part A 161A:162–165.
Raas-Rothschild A, Dijkhuizen T, Sikkema-Raddatz B, Werner M, Dagan J, Abeliovich D, Lerer I. 2009. The 8q22.1 microdeletion syndrome or Nablus mask-like facial syndrome: Report on two patients and review of the literature. Eur J Med Genet 52:140–144.
Duker AL, Ballif BC, Bawle EV, Person RE, Mahadevan S, Alliman S, Thompson R, Traylor R, Bejjani BA, Shaffer LG, Rosenfeld JA, Lamb AN, Sahoo T. 2010. Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader– Willi syndrome. Eur J Hum Genet 18:1196–1201.
Shieh JT, Aradhya S, Novelli A, Manning MA, Cherry AM, Brumblay J, Salpietro CD, Bernardini L, Dallapiccola B, Hoyme HE. 2006. Nablus mask-like facial syndrome is caused by a microdeletion of 8q detected by array-based comparative genomic hybridization. Am J Med Genet Part A 140:1267–1273.
Jain S, Yang P, Farrell SA. 2010. A case of 8q22.1 microdeletion without the Nablus mask-like facial syndrome phenotype. Eur J Med Genet 53:108–110.
Teebi AS. 2000. Nablus mask-like facial syndrome. Am J Med Genet 95:407–408.
Refinement of the 8q22.1 Microdeletion Critical Region Associated With Nablus Mask-Like Facial Syndrome Justin Overhoff,1 Marina M. Rabideau,1 Lynne M. Bird,2 Daniela N. Schweitzer,3,4 Karla Haynes,4 Roger A. Schultz,1 Lisa G. Shaffer,1 Jill A. Rosenfeld,1* and Jay W. Ellison1 1
Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, Washington Department of Pediatrics, University of California San Diego and Rady Children’s Hospital, San Diego, California
2 3
Department of Medical Genetics, Children’s Hospital Los Angeles, Los Angeles, California
4
Craniofacial and Cleft Center, Children’s Hospital Los Angeles, Los Angeles, California
Manuscript Received: 21 June 2013; Manuscript Accepted: 14 July 2013
TO THE EDITOR: The characteristic phenotype of Nablus mask-like facial syndrome (NMLFS), first described by Teebi [2000], consists of tight, glistening facial skin, blepharophimosis, ocular hypertelorism, abnormal ear architecture, sparse eyebrows, and an upswept frontal hairline. Some patients with NMLFS exhibit other features, including microcephaly, cryptorchidism, cleft palate, friendly demeanor, and a spectrum of neurologic phenotypes ranging from normal to complex motor and speech delays [Shieh et al., 2006; Raas-Rothschild et al., 2009]. The first genetic abnormalities associated with NMLFS were reported by Shieh et al. [2006], who described two affected individuals with chromosomal microdeletions spanning 8q21.3q22.1 detected by array comparative genomic hybridization (aCGH). Two subsequent reports described three additional probands with NMLFS and 8q22.1 deletions [Barber et al., 2008; RaasRothschild et al., 2009]; the commonly deleted region in all five patients defined a critical region of 2.8 Mb that presumably contains the causative gene(s) for the disorder (Fig. 1). Here we describe two individuals with the typical NMLFS phenotype who carry novel 8q22.1 microdeletions. One deletion reduces the size of the critical region associated with NMLFS. Informed consent was obtained to publish clinical data and images. Patient 1 is a 12-year-old male who was born prematurely at 27 weeks gestation following a pregnancy reportedly complicated by prenatal maternal street drug exposure. He is adopted; the family history is unknown. He was born with the characteristic NMLFS dysmorphic features, including tight, glistening facial skin with dimpling, blepharophimosis, arched eyebrows, bi-temporal narrowing, and dysplastic ears. His ears were low-set, posteriorly angulated, and had a prominent superior helix, hypoplastic inferior helix, a Y-shaped antihelix with a short trunk to the Y, and hypoplastic lobules (Fig. 2A,B). He presented at birth with a forme fruste cleft lip and high palate. His growth parameters have been within normal limits since birth. The patient has undergone surgical repair of penile chordee, bilateral inguinal hernias, bilateral cryptorchidism, and bilateral strabismus. Brain MRI was normal, and he
Ó 2013 Wiley Periodicals, Inc.
How to Cite this Article: Overhoff J, Rabideau MM, Bird LM, Schweitzer DN, Haynes K, Schultz RA, Shaffer LG, Rosenfeld JA, Ellison JW. 2014. Refinement of the 8q22.1 microdeletion critical region associated with Nablus masklike facial syndrome. Am J Med Genet Part A 164A:259–263.
has average intelligence. At age 12 years he had attention deficithyperactivity and obsessive-compulsive symptoms, chronic mild constipation, delayed fine motor and motor oral skills, and toe walking due to tight Achilles tendons. Patient 2 is an 11-week-old male with multiple congenital abnormalities who was born at 37 weeks gestation to phenotypically normal parents of Chinese and Palauan ancestry. Severe micrognathia, a large U-shaped cleft palate, low-set dysplastic ears, anterior cervical pits symmetrically located lateral to the trachea just below the mandible and another more inferiorly located on the right side of the neck, and cryptorchidism were noted. At birth, the
Conflict of interest: Justin Overhoff, Roger A. Schultz, and Jill A. Rosenfeld are employees of Signature Genomic Laboratories, a subsidiary of PerkinElmer, Inc. All other authors have no conflicts to declare. Marina M. Rabideau’s present address is InVitae, San Francisco, CA Lisa G. Shaffer’s present address is Paw Print Genetics, Genetic Veterinary Sciences, Inc, Spokane, WA Correspondence to: Jill Rosenfeld, M.S., LCGC, Signature Genomic Laboratories, PerkinElmer, Inc., 2820 North Astor Street, Spokane, WA 99207. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 20 November 2013 DOI 10.1002/ajmg.a.36163
259
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
FIG. 1. Schematic showing deletions involving 8q22.1. A: Full idiogram of chromosome 8 is across the top, with a partial idiogram of chromosome bands 8q21.3q22.1 below (hg19). Pink bar and vertical gray-shaded region show the NMLFS critical region. Orange and purple bars represent cases with and without NMLFS, respectively. Horizontal black lines extend through gaps in coverage to show maximum deletion sizes. B: Zoomed-in region, showing patients in this report and the narrowed NMLFS critical deletion region (dashed lines). Blue bars represent genes in the region.
patient weighed 2,880 g (25th–50th centile) and attained Apgar scores of 4 and 7 at 1 and 5 min, respectively. He had a normal echocardiogram, and a renal ultrasound revealed echogenic kidneys. A CT scan showed prominent fluid collection in the posterior fossa, decreased attenuation in the subcortical and periventricular white matter, and bilateral frontoparietal polymicrogyria (Fig. 2E,
F). At 11 weeks, all growth parameters were within normal range, though relative microcephaly was present (OFC 37.2 cm, 10th centile; crown-rump length 38 cm). A large right inguinal hernia and hypoplastic distal interphalangeal creases with recessed first toes were noted. He was alert, interactive, and focused on faces. His dysmorphic features were characteristic of NMLFS, including
OVERHOFF ET AL.
Mild: 2/11 0/7 2/10 4/11 4/11 3/11 1/9 1/11 4/11 1/11 1/7 0/11 (Continued) 4/6 4/6 4/4 6/6 5/5 4/4 4/4 6/6 4/6 6/6 2/6 2/3 þ NS þ Laterally sparse þ þ þ þ U-shaped NA þ þ þ Arched þ ; forme fruste cleft lip þ þ ; horizontal chin dimple þ High palate
Individuals with 8q22.1 deletions and NMLFSa Male (4), Female (2) 9 months to adult Varies (Fig. 1) De novo (4), maternal (1) Patient 2 Male 11 weeks 94,433,633–97,127,724 Unknown
Sex Age at evaluation Deletion coordinates (chr8, hg19) Inheritance Dysmorphic features Tight glistening facial skin Upswept frontal hair pattern Hypertelorism or telecanthus Highly arched, sparse eyebrows Flat, bulbous nasal tip Long philtrum Cheek dimples Blepharophimosis Micrognathia Abnormal ear shape Cleft palate Abnormal dentition
blepharophimosis, prominent cheeks with tight facial skin, and dysplastic ears. His ears were low-set, posteriorly angulated, and had slit-like external auditory canals, a prominent superior helix, a hypoplastic inferior helix, and a V-shaped antihelix (Fig. 2C,D). Oligonucleotide-based aCGH was performed using customdesigned SignatureChipOS, version 1 (Patient 1; 105K-feature, manufactured by Agilent Technologies, Santa Clara, CA) and version 2 (Patient 2; 135K-feature, manufactured by Roche NimbleGen, Madison, WI), according to previously described methods [Ballif et al., 2008; Duker et al., 2010]. Patients 1 and 2 have overlapping deletions within 8q22.1, 3.5 and 2.7 Mb, respectively (Table I, Fig. 1). Neither patient had other significant copy
Patient 1 Male 12 years 93,417,059–96,901,832 Unknown
FIG. 2. Phenotypic features of Patients 1 and 2. A,B: Patient 1 at 8 years of age. C,D: Patient 2 at 11 weeks of age. Both subjects show typical NMLFS facial features, including tight, glistening facial skin, laterally sparse eyebrows, telecanthus, blepharophimosis, bulbous nasal tip, micrognathia, and abnormal ears. E,F: Brain imaging for Patient 2 showed prominent fluid in the posterior fossa, decreased attenuation in subcortical and periventricular white matter, and bilateral frontoparietal polymicrogyria.
TABLE I. Clinical Features of Individuals With 8q22.1 Deletions
Individuals with 8q22.1 deletions and without NMLFSb Male (6), Female (5) 6 months to adult Varies (Fig. 1) De novo (8), maternal (2)
261
Non-contributory Family history
ADHD, attention deficit hyperactivity disorder; CHD, congenital heart defect; DD, developmental delay; ID, intellectual disability; NA, not applicable; NS, not specified; þ, feature present; , feature absent. a Five probands and one mother previously reported [Shieh et al., 2006; Barber et al., 2008; Raas-Rothschild et al., 2009]. b Nine probands and two mothers previously reported [Jain et al., 2010; Allanson et al., 2012; Debost-Legrand et al., 2013].
2/11 3 with autistic features; 1 with ADHD; 4 with CHD þ Born at 27 weeks, prenatal drug exposure, ADHD Unknown Happy/friendly disposition Other features
Brain abnormalities Postnatal microcephaly Cryptorchidism Hypoplastic/abnormal genitalia Widely spaced nipples Contractures/camptodactyly
DD/ID
4/4
1/2 4/5 3/3 3/4 2/4 2/4
þ (Fig. 2) þ; inguinal hernia þ NS Hypoplastic interphalangeal creases, 1st toes recessed NA Echogenic kidneys, cervical pits
Individuals with 8q22.1 deletions and NMLFSa 5/6 (variable severity) Patient 2 NA
Patient 1 þ; motor delay, normal intelligence Normal MRI þ; bilateral inguinal hernias þ; chordee Tight heel cords
TABLE I. (Continued )
1/1 4/10 2/6 3/10 0/5 1/9 (clubfeet)
AMERICAN JOURNAL OF MEDICAL GENETICS PART A Individuals with 8q22.1 deletions and without NMLFSb 11/11 (variable severity)
262
number abnormalities. Patient 2’s deletion did not include the centromeric 1 Mb of the previously defined critical region, allowing a narrowing of the NMLFS critical region to 1.84 Mb, from 94.43 to 96.27 Mb (hg19; Fig. 1). There have been reports of patients with deletions of all or part of the critical NMLFS region without the Nablus phenotype, who were tested for other indications (Fig. 1, Table I) [Jain et al., 2010; Allanson et al., 2012; Debost-Legrand et al., 2013]. In the most recent report, the authors concluded that because their patient did not display the phenotype, the deleted region in their patient does not contain critical genes for the disorder, thus significantly reducing the size of the critical region [Debost-Legrand et al., 2013]. However, Allanson et al. [2012] recently presented nine patients with deletions in the region (including two mother–child pairs), none of whom displayed the characteristic phenotype of NMLFS. Five of these patients were deleted for the entire region implicated by the previous reports of affected individuals. The authors concluded that deletion of the 8q22.1 region is necessary, but not sufficient, for development of the NMFLS phenotype. Another way of restating the conclusion of Allanson et al. [2012] is that the penetrance of the phenotype is reduced when deletions are present in the region. Therefore, unaffected individuals cannot be used to define the critical region. Here we report two individuals penetrant for the NMLFS phenotype, one narrowing the critical region for the disorder. Our Patient 2 was not deleted for the centromeric 1 Mb of the previously defined critical region, thereby reducing the critical region. Three genes (FLJ46284, TRIQK, and C8orf87) deleted in all other affected individuals are intact in our Patient 2, making it less likely that haploinsufficiency of one or more of these genes leads to the phenotype (though cis position effects could still conceivably alter their expression). Identification of additional affected individuals with smaller deletions or point mutations are needed to provide further insights into the pathogenesis of this disorder.
ACKNOWLEDGMENTS We thank Erin Dodge (Signature Genomics) for assistance with figure creation.
REFERENCES Allanson J, Smith A, Hare H, Albrecht B, Bijlsma E, Dallapiccola B, Donti E, Fitzpatrick D, Isidor B, Lachlan K, Le Caignec C, Prontera P, Raas-Rothschild A, Rogaia D, van Bon B, Aradhya S, Crocker SF, Jarinova O, McGowan-Jordan J, Boycott K, Bulman D, Fagerberg CR. 2012. Nablus mask-like facial syndrome: Deletion of chromosome 8q22.1 is necessary but not sufficient to cause the phenotype. Am J Med Genet Part A 158A:2091–2099. Ballif BC, Theisen A, McDonald-McGinn DM, Zackai EH, Hersh JH, Bejjani BA, Shaffer LG. 2008. Identification of a previously unrecognized microdeletion syndrome of 16q11.2q12.2. Clin Genet 74:469–475. Barber JC, Maloney VK, Huang S, Bunyan DJ, Cresswell L, Kinning E, Benson A, Cheetham T, Wyllie J, Lynch SA, Zwolinski S, Prescott L, Crow Y, Morgan R, Hobson E. 2008. 8p23.1 duplication syndrome; a novel genomic condition with unexpected complexity revealed by array CGH. Eur J Hum Genet 16:18–27.
OVERHOFF ET AL.
263
Debost-Legrand A, Eymard-Pierre E, Pebrel-Richard C, Gouas L, Goumy C, Giollant M, Ayed W, Tchirkov A, Francannet C, Vago P. 2013. A new case of 8q22.1 microdeletion restricts the critical region for Nablus masklike facial syndrome. Am J Med Genet Part A 161A:162–165.
Raas-Rothschild A, Dijkhuizen T, Sikkema-Raddatz B, Werner M, Dagan J, Abeliovich D, Lerer I. 2009. The 8q22.1 microdeletion syndrome or Nablus mask-like facial syndrome: Report on two patients and review of the literature. Eur J Med Genet 52:140–144.
Duker AL, Ballif BC, Bawle EV, Person RE, Mahadevan S, Alliman S, Thompson R, Traylor R, Bejjani BA, Shaffer LG, Rosenfeld JA, Lamb AN, Sahoo T. 2010. Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader– Willi syndrome. Eur J Hum Genet 18:1196–1201.
Shieh JT, Aradhya S, Novelli A, Manning MA, Cherry AM, Brumblay J, Salpietro CD, Bernardini L, Dallapiccola B, Hoyme HE. 2006. Nablus mask-like facial syndrome is caused by a microdeletion of 8q detected by array-based comparative genomic hybridization. Am J Med Genet Part A 140:1267–1273.
Jain S, Yang P, Farrell SA. 2010. A case of 8q22.1 microdeletion without the Nablus mask-like facial syndrome phenotype. Eur J Med Genet 53:108–110.
Teebi AS. 2000. Nablus mask-like facial syndrome. Am J Med Genet 95:407–408.
