Deletion of chromosome 8q22.1, a critical region for Nablus mask‐like facial syndrome: Four additional cases support a role of genetic modifiers in the manifestation of the phenotype

Jamuar, Saumya Shekhar; Duzkale, Hatice; Gökçe, Aysun; Zhang, Chengsheng; High, Frances A.; Kaban, Leonard B.; Bhattacharya, Sameek; Crandall, Barbara F.; Kantarci, Sibel; Stoler, Joan M.; Lin, Angela E.

doi:10.1002/ajmg.a.36848

Cited by 9 publications

(6 citation statements)

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“…Thus, these data suggest that the pathophysiological mechanism behind this rare condition may be more complicated than the simple binary patterns Gregor Mendel described in 1864 (Allanson et al, ; Jamuar et al, ; Overhoff et al, ). In the following section we discuss potential mechanisms (one‐locus, two‐locus, epigenetic, and environmental) for Nablus syndrome.…”

Section: Molecular Pathogenesismentioning

confidence: 78%

“…In 2009, Raas‐Rothschild and colleagues were able to confirm the presence of a deletion of 3.37 Mb at chromosome position 8q22.1 in Teebi's original patient (Raas‐Rothschild et al, ; Teebi, ). Microarray analysis from reported individuals with Nablus syndrome, including the two mother–son pairs, demonstrate an overlapping and contiguous gene deletion at chromosome 8q22.1 in all affected individuals (see Table and Figure ; Allanson et al, ; Barber et al, ; Jamuar et al, ; Overhoff et al, ; Raas‐Rothschild et al, ; Shieh et al, ).…”

Section: Molecular Pathogenesismentioning

confidence: 99%

“…Comparative analysis of microarray data between affected individuals has identified a minimal critical region at 8q of 1.84 Mb (94.43–96.27 Mb on genomic build GRCh37/hg19; Jamuar et al, ), which contains more than 20 genes (Figure ). Seventeen of these are coding genes, three are noncoding RNAs ( LINC00535 , cORF69 , and LOC100288748 ), and three are microRNAs ( MIR378D2 , MIR3150B , and MIR3150A ) and a clone called TSTI2008046 ( AX747981 ).…”

Section: Molecular Pathogenesismentioning

confidence: 99%

“…Interestingly, these individuals include two mother–child pairs with a deletion of most or all of the critical region. Although one member of each pair is said to have mildly tight or thick skin, they lack the impairment of facial expression necessary for a diagnosis of Nablus syndrome (Table ; Allanson et al, ; Debost‐Legrand et al, ; Jain, Yang, & Farrell, ; Jamuar et al, ).…”

Section: Molecular Pathogenesismentioning

confidence: 99%

“…In 2002, we were the first to report the familial occurrence of Nablus syndrome in an affected 4‐year‐old male and his mother ( Figure ; Allanson, ). Since the 2002 publication, there have been nine reports of affected individuals; seven are individuals with no family history, one of whom is adopted (Jamuar et al, ; Overhoff et al, ; Raas‐Rothschild et al, ; Salpietro et al, 2003; Shieh et al, 2006). There is an additional mother–son pair, and the mother may have had an affected maternal half‐brother (Barber et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Nablus syndrome: Easy to diagnose yet difficult to solve

et al. 2018

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Nablus syndrome was first described by the late Ahmad Teebi in 2000, and 13 individuals have been reported to date. Nablus syndrome can be clinically diagnosed based on striking facial features, including tight glistening skin with reduced facial expression, blepharophimosis, telecanthus, bulky nasal tip, abnormal external ear architecture, upswept frontal hairline, and sparse eyebrows. However, the precise genetic etiology for this rare condition remains elusive. Comparative microarray analyses of individuals with Nablus syndrome (including two mother-son pairs) reveal an overlapping 8q22.1 microdeletion, with a minimal critical region of 1.84 Mb . Whereas this deletion is present in all affected individuals, 13 individuals without Nablus syndrome (including two mother-child pairs) also have the 8q22.1 microdeletion that partially or fully overlaps the minimal critical region. Thus, the 8q22.1 microdeletion is necessary but not sufficient to cause the clinical features characteristic of Nablus syndrome. We discuss possible explanations for Nablus syndrome, including one-locus, two-locus, epigenetic, and environmental mechanisms. We performed exome sequencing for five individuals with Nablus syndrome. Although we failed to identify any deleterious rare coding variants in the critical region that were shared between individuals, we did identify one common SNP in an intronic region that was shared. Clearly, unraveling the genetic mechanism(s) of Nablus syndrome will require additional investigation, including genomic and RNA sequencing of a larger cohort of affected individuals. If successful, it will provide important insights into fundamental concepts such as variable expressivity, incomplete penetrance, and complex disease relevant to both Mendelian and non-Mendelian disorders. K E Y W O R D Sblepharophimosis, bulbous nose, deletion 8q, Nablus syndrome, sparse eyebrows, telecanthus

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Section: Molecular Pathogenesismentioning

confidence: 78%

Section: Molecular Pathogenesismentioning

confidence: 99%

Section: Molecular Pathogenesismentioning

confidence: 99%

Section: Molecular Pathogenesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nablus syndrome: Easy to diagnose yet difficult to solve

et al. 2018

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Nablus mask‐like facial syndrome: Report of an atypical case with 8q21.3–q22.1 deletion

Mitrakos,

Kekou,

Tilemis

et al. 2024

American J of Med Genetics Pt A

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Nablus mask‐like facial syndrome (NMLFS) is a rare condition characterized by unique facial features, initially described in a 4‐year‐old boy from Nablus, Palestine. These features include expressionless facial appearance, tight facial skin, blepharophimosis, sparse eyebrows, and a flat nose. Genetic studies have identified a deletion of 8q22.1 as the cause of the syndrome, however while 26 patients have been reported with the deletion, only 13 displayed the characteristic facial features. Here we report on a 35‐year‐old male with 8q21.3–q22.1 deletion identified by whole exome sequencing and Chromosomal microarray analysis (CMA) that presents with typical and atypical features, including neurodevelopmental disorder, mild facial features, and myopathy, which has not been described in a patient with NMLFS to date. Further research will be required to understand the underlying pathogenetic mechanism of this rare genetic disorder.

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Unsolved recognizable patterns of human malformation: Challenges and opportunities

2018

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Due to the efforts of the clinical and scientific communities and boosted by recent advances in genetic technologies, we now understand the molecular mechanisms underlying most of the frequent and recognizable human malformation syndromes. However, some well‐established human malformation syndromes remain without a molecular diagnosis despite intensive investigation. This issue of Seminars mines the phenotypic entries in OMIM and estimates that of the documented 2,034 unsolved entries likely to represent a rare genetic disease, only 160 are well‐established and possibly amenable to investigation. This issue also reviews well‐characterized and extensively investigated human malformation syndromes and associations that remain unsolved, including the following: Dubowitz syndrome (MIM 223370%), Hallermann–Streiff syndrome (MIM 234100%), PHACE syndrome (MIM 606519), Oculocerebrocutaneous syndrome (MIM 164180), Aicardi syndrome (MIM 304050%), Gomez–Lopez–Hernandez syndrome and Rhombencephalosynapsis (MIM 601853%), VACTERL (MIM 192350%), and Nablus syndrome (MIM #608156). Possible explanations for their intractability to molecular diagnosis are explored, including genetic and phenotypic heterogeneity, mosaicism, epigenetics, gene–environment interactions, and other non‐Mendelian contributions. Finally, this issue of Seminars presents a path forward for these unsolved rare conditions and suggests a renewed focus on solving amendable OMIM disorders. It is clear that the way forward will require new technologies, global cooperation, and data sharing; these will also be necessary to help reach the vision of the International Rare Diseases Research Consortium (IRDiRC), that is to enable all people living with a rare disease to receive an accurate diagnosis, care and available therapy within 1 year of coming to medical attention.

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Deletion of chromosome 8q22.1, a critical region for Nablus mask‐like facial syndrome: Four additional cases support a role of genetic modifiers in the manifestation of the phenotype

Cited by 9 publications

References 10 publications

Nablus syndrome: Easy to diagnose yet difficult to solve

Nablus syndrome: Easy to diagnose yet difficult to solve

Nablus mask‐like facial syndrome: Report of an atypical case with 8q21.3–q22.1 deletion

Unsolved recognizable patterns of human malformation: Challenges and opportunities

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