• Users Online: 539
  • Print this page
  • Email this page


 
 
Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 7  |  Issue : 1  |  Page : 1-6

Clinical genetics revisited: effect of new techniques (next-generation sequencing, comparative genomic hybridization) on previous diagnoses


Institut Jerome Lejeune, Centre de Ressources Biologiques BioJeL, Paris, France

Date of Submission24-Nov-2017
Date of Acceptance01-Dec-2017
Date of Web Publication26-Mar-2018

Correspondence Address:
Andre Megarbane
Institut Jerome Lejeune, 75015 Paris
France
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/MXE.MXE_3_17

Rights and Permissions
  Abstract 

Using Next Generation Sequencing technics, we revisited 42 personal publications on rare or firstly described syndromes. Four syndromes were found to have been erroneously classified as new, six newly described syndromes were found to be allelic to previously known syndromes, eight cases were solved, and 23 were still unexplained. In few families at least 2 genes were involved in the pathogenicity of the disease. The extreme rarity of the association of more than one mutated gene explains the absence of any other reported cases.

Keywords: Syndromes, CGH, WES, NGS


How to cite this article:
Megarbane A. Clinical genetics revisited: effect of new techniques (next-generation sequencing, comparative genomic hybridization) on previous diagnoses. Middle East J Med Genet 2018;7:1-6

How to cite this URL:
Megarbane A. Clinical genetics revisited: effect of new techniques (next-generation sequencing, comparative genomic hybridization) on previous diagnoses. Middle East J Med Genet [serial online] 2018 [cited 2024 Mar 29];7:1-6. Available from: http://www.mxe.eg.net/text.asp?2018/7/1/1/228075


  Body Top


Simple molecular technologies have changed the clinical diagnostic approach to many genetic disorders. With the adoption of newer molecular techniques, such as the array comparative genomic hybridization and the whole exome sequencing (WES)/whole genome sequencing, the identification of the molecular origin of various disorders has improved. After 25 years of practice in medical genetics, I thought that it might be interesting to revisit my personal publications on rare or firstly described syndromes.

A total of 42 publications were selected, which were divided into four groups. The first one regroups papers on newly described syndromes, found later on to be not new. The second group is that of newly described syndromes found later on to be allelic to other syndromes. The third group is that of newly described syndromes of unknown etiology finally resolved. The fourth group includes new diagnoses not (yet) molecularly identified.

Syndromes erroneously classified as new

Four syndromes were found to have been erroneously classified as new [Table 1]. The family reported with an unusual form of ectodermal dysplasia (Mégarbané et al., 1998a) was found later to have a mutation in the WNT10A, confirming the diagnosis of Odonto-Onycho-Dermal Dysplasia (OMIM 257980). This family is still listed in OMIM under the number #602401 as ectodermal dysplasia hair/tooth/nail type 8.
Table 1: Reported syndromes erroneously classified

Click here to view


When Faivre et al. (2000) mapped the acromesomelic dysplasia Maroteaux type, in one of the investigated family, a Lebanese family, it was found not to map to 9p13-q12 like all others, and they discussed the clinical and genetic heterogeneity of this disease (OMIM 602875). Few years later, after reexamining this family, an autosomal recessive Robinow syndrome was suspected and confirmed by molecular analysis (Mehawej et al., 2012).

In 2005, two siblings were described with mild intellectual disability, microcephaly, microtia, cleft palate, and esophageal atresia in one. They were considered to have a new autosomal recessive otofacial syndrome with midline malformations (Mégarbané et al., 2005). Guion-Almeida et al. (2006) reported on two Brazilian cases and reviewed two previously reported patients with mandibulofacial dysostosis, microcephaly, unusual ears with skin tags, and cleft palate, describing a new autosomal dominant mandibulofacial dysostosis. Both entities presented close clinical features, but the mode of inheritance was different. When mutations in the EFTUD2 gene were found in Guion-Almeida cases (Lines et al., 2012), the gene was sequenced in the Lebanese patients, and a mutation at the heterozygous state was found. None of the parents had that mutation, and false paternity was ruled out, confirming the presence of a germline mosaicism in the Lebanese family.

Chouery et al. (2010)reported on a Lebanese consanguineous family where two affected sisters were considered to have a new sclerosing bone dysplasia. Patients presented with short stature, severe genu varum, cranial hyperostosis, and a very high bone density. After genotyping and WES, a homozygous mutation disrupting the initiation codon of the DMP1 gene (OMIM 600980) was identified, confirming that it was a case of hypophosphatemic rickets (Gannagé-Yared et al., 2014). In fact, some cases of hypophosphatemic rickets may develop with age an increase in bone density and bone overgrowth (Gannagé-Yared et al., 2014).


  Newly described syndromes allelic to previously known syndromes Top


Six newly described syndromes were found to be allelic to previously known syndromes [Table 2]. Two brothers, offsprings of nonconsanguineous Lebanese parents, who had microcephaly, cutis verticis gyrata of the scalp, retinitis pigmentosa, cataracts, sensorineural deafness, intellectual disability, and kyphoscoliosis were reported by Mégarbané et al. (2001). Later on, a homozygous splice site mutation in VPS13B, a gene responsible for Cohen syndrome, was found (Mégarbané et al., 2009). Cutis verticis gyrata and sensorineural deafness are not known to occur in Cohen syndrome (Mégarbané et al., 2009) [Table 2].
Table 2: Syndromes solved molecularly

Click here to view


In 2004 and 2007, two Lebanese families were reported as having a newly recognized chondrodysplasia with multiple dislocations (CDMD 'Megarbane type'). These patients were found later to have mutations in the CHST3 gene (Unger et al., 2010), known to be responsible of the Larsen autosomal recessive syndrome and other rare entities such as the spondyloepiphyseal dysplasia Omani type, the humerospinal dysostosis, and the chondrodysplasia with multiple dislocations, all now grouped under the same group, the CHST3-related skeletal dysplasia.

CAMOS syndrome (Cerebellar Ataxia with Mental retardation, Optic atrophy and Skin abnormalities) (OMIM: 606737) is a rare autosomal recessive entity that has been described only once, in five affected individuals from a large inbred Lebanese family (Mégarbané et al., 2001a). A homozygous c. 3136G>A (p. Gly1046Arg) missense mutation in ZNF592 was found as the likely molecular defect underlying CAMOS (Nicolas et al., 2010). Recently, the molecular basis of CAMOS was revisited by redefining WDR73 (OMIM: 616144) as the disease causing gene in that Lebanese family (Vodopiutz et al., 2015). This gene has been implicated in the Galloway Mowat syndrome, a rare autosomal recessive disease, characterized by microcephaly with brain anomalies, including cerebellar atrophy in some cases, intellectual disability, and early-infantile-onset nephrotic syndrome (OMIM: 215300). A homozygous c. 1039C>T missense mutation in WDR73 exon 8 was found and considered as disease causing for CAMOS, instead of the previously published c. 3136G>A (p. Gly1046Arg) missense mutation in ZNF592 (Vodopiutz et al., 2015).

Two siblings with multiple cranial nerve neuropathies, microcephaly, neurological degeneration, and 'fork and bracket sign' in the brain MRI were reported by Mégarbané et al. (2010). Later on, using a WES, a mutation at a homozygous state p.L335P was found in the SBF1 gene (set binding factor-1) (Romani et al., 2016). The latter was found to be involved in autosomal recessive Charcot–Marie–Tooth disease type 4B3 (Nakhro et al., 2013). This allowed to further expand the phenotypic spectrum of SBF1-associated CMT and include the 'fork and bracket' syndrome in it.


  Mysterious cases finally solved Top


Eight of 42 (19%) cases published as new syndromes and discussed in this paper were solved using new molecular genetic approaches [Table 3].
Table 3: Newly described syndromes allelic to previously known syndromes

Click here to view


A young boy reported by Mégarbané and Chammas (1997) was considered to have a newly described entity very close to a patient reported by de Die-Smulders et al. (1993). Using array comparative genomic hybridization, a gain on chromosome 9 on 9q33.3q34.3 was found (Callier et al., 2013). Unfortunately, we do not have any feedback for the patient reported by de Die-Smulders et al. (1993) to assert whether indeed both patients present the same chromosomal abnormality.

Mégarbané et al. reported in 1998 a brother and three sisters with a syndrome characterized by skeletal abnormalities, mental retardation, sensorineural deafness, cataracts, and microcephaly. Megarbane et al., 1998b. There was scoliosis with bowed tibiae, dislocation of the elbows, and short fourth metacarpals. In 2014, Makrythanasis et al. (2014) reported a novel homozygous mutation in the FGFR3 gene in two brothers with tall stature, camptodactyly, hearing loss, and skeletal abnormalities mainly lateral tibial deviation, all features identically present in the family previously reported by Mégarbané et al. (1998). Although, the gene could not be tested in the latter, we believe that it is the same entity and that it could be more accurate to change the entry of this report in OMIM.

In 1999, Mégarbané et al. described a Lebanese family in which 12 persons had secundum atrial defect and various cardiac and noncardiac anomalies with an autosomal dominant mode of inheritance. After the ACTC1 gene was identified to be mutated in Swedish families, segregating autosomal dominant secundum atrial septal defect (Matsson et al., 2008), we analyzed this gene in the Lebanese family and also found a mutation (Augière et al., 2015).

In 2002, Mégarbané et al. reported on a new syndrome in a boy characterized by short stature, motor developmental delay, wide nasal bridge, bilateral periorbital edema, everted lower lip, brachydactyly, large interphalangeal articulations, drumstick extremities of the fingers, bilateral simian crease, clinodactyly of the fifth fingers, painful joints, subcutaneous nodules all over the body, and recurrent episodes of fever of unknown origin. A few years later, four patients were reviewed with similar symptoms, and the syndrome was named CANDLE for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (Torrelo et al., 2010). The current known cause for this disorder is a mutation in the proteasome genes (Brehm et al., 2015).

In two unrelated Lebanese families with a rare lethal spondylometaphyseal dysplasia (Mégarbané-Dagher-Melki type; OMIM 613320), Mehawej et al. (2014) identified a homozygous missense mutation in the MAGMAS (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) gene. Since that time, another case has been published (Moosa et al., 2016), and this type of chondrodysplasia was added in the last version of classification of genetic skeletal disorders (Bonafe et al., 2015).


  Mysterious syndromes still unexplained Top


Twenty-three of 42 (54.5%) cases remain unsolved while writing this article. In almost all of those families, a WES was performed, but no causative gene was found. What is interesting is that in some families, class 3 variations (Variant of Uncertain significance) were found in at least two genes. We believe that additional features seen in specific syndromes and the extreme rarity of some clinical association, as seen in some of our reports, might be explained with what Lupski et al. (2011) has called 'clan genomics', that is the idea that there are unique combinations of rare variants specific to a family lineage that can have a causative role in disease. Indeed, it is now a common view that several rare variants, 'in combination', cause a disease, with one 'Highly penetrant Mendelizing Variant' responsible for the disease, and other variants modifying the phenotype (Gonzaga-Jauregui et al., 2015) [Table 4].
Table 4: The not solved cases

Click here to view


One example is the homozygous ZNF592 missense mutation, contributory to CAMOS. The combination of the WDR73 and ZNF592 variants defines variation in the phenotype. The extreme rarity of this association explains the absence of any other reported cases. However, we cannot exclude the possibility that the p. Gly1046Arg variation in ZNF592 might have additive or modifying effects on the CAMOS phenotype. Whether CAMOS is part of the phenotypic spectrum of WDR73-associated diseases or is allelic to these diseases remains an open question.


  Conclusion Top


In conclusion, we have shown the importance in the use of new techniques in molecular biology to revisit some old diagnosis. These new molecular tests in the era of NGS sequencing will not only provide a powerful means for identifying mutated genes responsible for hereditary disease but also become a veritable gold mine in the quest to understand phenotypic heterogeneity and the modifying effects of mutations (Shamia et al., 2015), especially in the consanguineous families. [65]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Atrouni A, Darazé A, Tamraz J, Cassia A, Caillaud C, Mégarbané A (2003). Leukodystrophy associated with oligodontia in a large inbred family: Fortuitous association or new entity? Am J Med Genet 118A:76–81.  Back to cited text no. 1
    
2.
Augière C, Mégy S, El Malti R, Boland A, El Zein L, Verrier B, et al. (2015). Novel Alpha Cardiac Actin (ACTC1) Mutation mapping to a domain in close contact with myosin heavy chain leads to a variety of congenital heart defects, arrhythmia and possibly midline defects. PLoS One 10:e0127903.  Back to cited text no. 2
    
3.
Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, et al. (2015). Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A 167A:2869–2892.  Back to cited text no. 3
    
4.
Brehm A, Liu Y, Sheikh A, Marrero B, Omoyinmi E, Zhou Q, et al. (2015). Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest 125:4196–4211.  Back to cited text no. 4
    
5.
Callier P, Aral B, Hanna N, Lambert S, Dindy H, Ragon C, et al. (2013). Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability. Clin Genet 84:507–521.  Back to cited text no. 5
    
6.
Chouery E, Pangrazio A, Frattini A, Villa A, van Wesenbeeck L, Piters E, et al. (2010). A new familial sclerosing bone dysplasia. J Bone Miner Res 25:676–680.  Back to cited text no. 6
    
7.
De Die-Smulders C, Vles H, Fryns JP (1993). Characteristic facial dysmorphism, arachnodactyly and mental handicap in two unrelated girls: a distinct MCA/MR syndrome? Genet Couns 4:165–167.  Back to cited text no. 7
    
8.
Faivre L, Le Merrer M, Mégarbané A, Gilbert B, Mortier G, Cusin V, et al. (2000). Exclusion of chromosome 9 helps identifiying mild variants of acromesomelic dysplasia maroteaux type. J Med Genet 37:52–54.  Back to cited text no. 8
    
9.
Gannagé-Yared MH, Makrythanasis P, Chouery E, Sobacchi C, Mehawej C, Santoni FA, et al. (2014). Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia. Bone 68:142–145.  Back to cited text no. 9
    
10.
Gonzaga-Jauregui C, Harel T, Gambin T, Kousi M, Griffin LB, Francescatto L, et al. (2015). Exome sequence analysis suggests that genetic burden contributes to phenotypic variability and complex neuropathy. Cell Reports 12:1169–1183.  Back to cited text no. 10
    
11.
Guion-Almeida ML, Zechi-Ceide RM, Vendramini S, Tabith Júnior A (2006). A new syndrome with growth and mental retardation, mandibulofacialdysostosis, microcephaly, and cleft palate. Clin Dysmorphol 15:171–174.  Back to cited text no. 11
    
12.
Lines MA, Huang L, Schwartzentruber J, Douglas SL, Lynch DC, Beaulieu C, et al. (2012). Haploin sufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacialdysostosis with microcephaly. Am J Hum Genet 90:369–377.  Back to cited text no. 12
    
13.
Lupski JR, Belmont JW, Boerwinkle E, Gibbs RA (2011). Clan genomics and the complex architecture of human disease. Cell 147:32–43.  Back to cited text no. 13
    
14.
Makrythanasis P, Temtamy S, Aglan M, Otaify GA, Hamamy H, Antonarakis SE (2014). A novel homozygous mutation in FGFR3 causes tall stature, severe lateral tibial deviation, scoliosis, hearing impairment, camptodactyly, and arachnodactyly. Hum Mutat 35:959–963.  Back to cited text no. 14
    
15.
Matsson H, Eason J, Bookwalter CS, Klar J, Gustavsson P, Sunnegårdh J, et al. (2008). Alpha-cardiac actin mutations produce atrial septal defects. Hum Mol Genet 17:256–265.  Back to cited text no. 15
    
16.
Mégarbané A (2001). A new familial syndrome with abnormal facial features, abnormal EEG, and mental retardation. Clin Dysmorphol 10:129–133.  Back to cited text no. 16
    
17.
Mégarbané A (2003). Unknown diagnosis in two male cousins with facial abnormalities, optic atrophy, abnormal EEG, and severe psychomotor retardation. Am J Med Genet 116A:381–384.  Back to cited text no. 17
    
18.
Mégarbané A (2007). Osseous dysplasia with severe short stature, multiple dislocations, and delayed bone age: report on a second Lebanese patient. Am J Med Genet A 143:1782–1787.  Back to cited text no. 18
    
19.
Mégarbané A, Loiselet J (1996). A severe congenital neonatal progeroid syndrome. Clin Genet 51:200–204.  Back to cited text no. 19
    
20.
Mégarbané A, Abi-Moussa M (1997). Brachytelephalangy, short stature, mental retardation and dysmorphic features in two sibs. New MCA/MR syndrome? Genet Couns 8:127–132.  Back to cited text no. 20
    
21.
Mégarbané A, Chammas K (1997). Severe mental retardation and marfanoid habitus in a young Lebanese male. A diagnostic challenge. Genet Couns 8:195–200.  Back to cited text no. 21
    
22.
Mégarbané A, Cormier-Daire V (2001). Short stature, peculiar face, joints laxity, joints dislocation, and mental retardation in two sibs. A new MCA/MR syndrome. Am J Med Genet 102:153–156.  Back to cited text no. 22
    
23.
Mégarbané A, Ghanem I (2002). Tibial/femoral hypoplasia with 'hook' pelvis: a potentially unique dysostosis. Am J Med Genet 112:394–396.  Back to cited text no. 23
    
24.
Mégarbané A, Ghanem I (2004). A newly recognized chondrodysplasia with multiple dislocations. Am J Med Genet 130A:107–109.  Back to cited text no. 24
    
25.
Mégarbané A, Sayad R (2007). Early lethal autosomal recessive enterocolitis: report of a second family. Clin Genet 71:89–90.  Back to cited text no. 25
    
26.
Mégarbané A, Le Merrer M, El Kallab K (1997). Ptosis, down-slanting palpebral fissures, hypertelorism, seizures and mental retardation: a possible new MCA/MR syndrome. Clin Dysmorphol 6:239–244.  Back to cited text no. 26
    
27.
Mégarbané A, Noujeim Z, Fabre M, der Kaloustian V (1998a). New form of hidrotic ectodermal dysplasia in a Lebanese family. Am J Med Genet 75:196–199.  Back to cited text no. 27
    
28.
Mégarbané A, Kharrat K, Kreichaty G (1998b). Four sibs with multiple osseous malformations, cataract, deafness and mental retardation: a new MCA/MR syndrome. J Med Genet 35:755–758.  Back to cited text no. 28
    
29.
Mégarbané A, Haddad-Zebouni S, Nabbout R, Khoury A, Traboulsi E (1999a). Microcephaly, microphthalmia, short stature and severe psychomotor retardation in two male cousins: a new MCA/MR syndrome? Am J Med Genet 83:83–87.  Back to cited text no. 29
    
30.
Mégarbané A, Stephan E, Kassab R, Ashoush R, Salem N, Bouvagnet P, Loiselet J (1999b). Autosomal dominant atrial septal defect associated to cardiac and non-cardiac defects. a new midline cardiac disorder. Am J Med Genet 83:193–200.  Back to cited text no. 30
    
31.
Mégarbané A, Bou Farah C, Nabbout R (1999c). Unknown syndrome in two male sibs with facial dysmorphia, camptodactyly, fifth fingers clinodactyly, 2/3 toes syndactyly and mental retardation. Genet Couns 10:183–188.  Back to cited text no. 31
    
32.
Mégarbané A, Delague V, Salem N, Loiselet J (1999d). Autosomal recessive cerebellar hypoplasia with a short stature in a large inbred Lebanese family. Am J Med Genet 87:88–90.  Back to cited text no. 32
    
33.
Mégarbané A, Khalil G, Waked N, Mezzina M, Caillaud C, Rotig A, Loiselet J (1999e). Congenital deafness, myoclonus epilepsy, psychiatric behavior. Further delineation of the Latham-Munro syndrome or new syndrome? Am J Med Genet 87:289–293.  Back to cited text no. 33
    
34.
Mégarbané A, Waked N, Chouery E, BouMoglabey Y, Saliba N, Mornet E, et al. (2001). Microcephaly, cutis verticis gyrata of the scalp retinitis pigmentosa, cataracts, sensorineural deafness, and mental retardation in two brothers: a new syndrome. Am J Med Genet 98:244-249.  Back to cited text no. 34
    
35.
Mégarbané A, Delague V, Ruchoux MM, Rizkallah E, Viollet L, Rouaix-Emery N, Urtizberea A (2001a). New autosomal recessive cerebellar ataxia syndrome in a large inbred Lebanese family. Am J Med Genet 101:135–141.  Back to cited text no. 35
    
36.
Mégarbané A, Ruchoux MM, Loeys B, Ayoub N, Nuytinck. L (2001b). Short stature, abnormal face, joints laxity, dislocation, hernias, delayed bone age, and severe psychomotor retardation in two sibs. A new MCA/MR syndrome. Am J Med Genet 104:221–224.  Back to cited text no. 36
    
37.
Mégarbané A, Sanders A, Torbey PH (2002). An autoinflammatory syndrome associated with short stature and dysmorphic features in a young boy. J Rheumatol 29:1084–1087.  Back to cited text no. 37
    
38.
Mégarbané A, Ghanem I, Romana S, Gosset P, Caillaud C (2002a). Congenital contractures, short stature, abnormal face, microcephaly, scoliosis, hip dislocation, and severe psychomotor retardation in two unrelated girls. A new MCA/MR syndrome? Genet Counsel 13:123–131.  Back to cited text no. 38
    
39.
Mégarbané A, Hersh J, Chouery E, Fabre M (2002b). Craniosynostosis, telecanthus, scalp hair abnormalities, sensorineural deafness in two sibs. Am J Med Genet 109:323–327.  Back to cited text no. 39
    
40.
Mégarbané A, Ghanem I, Rizk T, Jabbour P (2002c). Prenatal growth deficiency with narrowness of the cervical spine, subglottic stenosis, hip dislocation, and severe delayed bone ossification: a new skeletal dysplasia. Am J Med Genet 112:70–74.  Back to cited text no. 40
    
41.
Mégarbané A, Vabres P, Slaba S, Smahi A, Loeys B, Okais N (2002d). Linear and whorled nevoid hypermelanosis with bilateral giant cerebral aneurysms. Am J Med Genet 112:95–98.  Back to cited text no. 41
    
42.
Mégarbané A, Haddad J, Lyonnet S, Clayton-Smith J (2003a). Child with overgrowth, pigmentary streaks, polydactyly, and intestinal lymphangiectasia: macrocephaly-cutis marmorata telangiectatica congenita syndrome or new disorder? Am J Med Genet 116A:184–187.  Back to cited text no. 42
    
43.
Mégarbané A, Rassi S, Chouery E, Delague V, Perez de Nanclares Leal G, Tabet M, et al. (2003b). A new dominant branchiogenic-deafness syndrome with internal auditory canal hypoplasia and abnormal extremities. Am J Med Genet 120A:276–282.  Back to cited text no. 43
    
44.
Mégarbané A, Rassi S, Estephan F, Kouba-Hreich E (2004a) Post-natal short stature, short limbs, brachydactyly, facial abnormalities, and delayed bone age: a new syndrome? Am J Med Genet 125A:57–60.  Back to cited text no. 44
    
45.
Mégarbané A, Daou L, Mégarbané H, Cave H, Chouery E, Verloes A (2004b). New autosomal recessive syndrome with short stature and facio-auriculo-thoracic malformations. Am J Med Genet 128A:414–417.  Back to cited text no. 45
    
46.
Mégarbané A, Melick N, Daou L (2004c). A newly recognized skeletal dysplasia with rhizomelic limbs and retinitis pigmentosa. Am J Med Genet 130A:176–179.  Back to cited text no. 46
    
47.
Mégarbané A, Chouery E, Rassi S, Delague V (2005). A new autosomal recessive otofacial syndrome with midline malformations. Am J Med Genet A 132A:398–401.  Back to cited text no. 47
    
48.
Mégarbané A, Ghanem I, Waked N, Dagher F (2006). A newly recognized autosomal recessive syndrome with short stature and oculoskeletal involvement. Am J Med Genet 140A:1491–1496.  Back to cited text no. 48
    
49.
Mégarbané A, Dagher R, Melki I (2008a). Sib pair with previously unreported skeletal dysplasia. Am J Med Genet A 146A:2916–2919.  Back to cited text no. 49
    
50.
Mégarbané A, Samaras L, Chédid R, Chouery E, Chrétien D, Caillaud C, et al. (2008b). Developmental delay, dysmorphic features, neonatal spontaneous fractures, wrinkled skin, and hepatic failure: a new metabolic syndrome? Am J Med Genet A 146A:3198–3201.  Back to cited text no. 50
    
51.
Mégarbané A, Slim R, Nürnberg G, Ebermann I, Nürnberg P, Bolz HJ (2009). A novel VPS13B mutation in two brothers with Cohen syndrome, cutis verticisgyrata and sensorineural deafness. Eur J Hum Genet 7:1076–1079.  Back to cited text no. 51
    
52.
Mégarbané A, Dorison N, Rodriguez D, Tamraz J (2010). Multiple cranial nerve neuropathies, microcephaly, neurological degeneration, and 'fork and bracket sign' in the MRI: a distinct syndrome. Am J Med Genet A 152A:2297–2300.  Back to cited text no. 52
    
53.
Mégarbané A, Chouery E, Mignon-Ravix C, ElSabbagh S, Corbani S, Ghoch JA (2011). Ambiguous genitalia, microcephaly, seizures, bone malformations, and early death: a distinct MCA/MR syndrome. Am J Med Genet A 155:1147–1151.  Back to cited text no. 53
    
54.
Mégarbané A, Hanna N, Chouery E, Jalkh N, Mehawej C, Boileau C (2012). Marfanoid habitus, inguinal hernia, advanced bone age, and distinctive facial features: a new collagenopathy? Am J Med Genet A 158A:1185–1189.  Back to cited text no. 54
    
55.
Mehawej C, Delahodde A, Mehawej C, Chouery E, Maalouf D, Baujat G, et al. (2012). Identification of a novel causative mutation in the ROR2 gene in a Lebanese family with a mild form of recessive Robinow syndrome. Eur J Med Genet 55:103–108.  Back to cited text no. 55
    
56.
Mehawej C, Legeai-Mallet L, Delague V, Kaci N, Desvignes JP, Kibar Z, et al. (2014). The impairment of MAGMAS function in human is responsible for a severe skeletal dysplasia. PLoS Genet 10:e1004311.  Back to cited text no. 56
    
57.
Moosa S, Fano V, Obregon MG, Altmüller J, Thiele H, Nürnberg P, et al. (2016). novel homozygous PAM16 mutation in a patient with a milder phenotype and longer survival. Am J Med Genet A. 170(9):2436–2439.  Back to cited text no. 57
    
58.
Nakhro K, Park JM, Hong YB, Park JH, Nam SH, Yoon BR, et al. (2013). SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3. Neurology 81:165–173.  Back to cited text no. 58
    
59.
Nicolas E, Poitelon Y, Chouery E, Salem N, Levy N, Mégarbané A, Delague V (2010). CAMOS, a nonprogressive, autosomal recessive, congenital cerebellar ataxia, is caused by a mutant zinc-finger protein, ZNF592. Eur J Hum Genet 18:1107–1113.  Back to cited text no. 59
    
60.
Ravel A, Chouery E, Stora S, Jalkh N, Villard L, Temtamy S, Mégarbané A (2011). How many entities exist for the spectrum of disorders associated with brachydactyly, syndactyly, short stature, microcephaly, and intellectual disability? Am J Med Genet A 155:880–884.  Back to cited text no. 60
    
61.
Romani M, Mehawej C, Mazza T, Mégarbané A, Valente EM (2016). 'Fork and bracket' syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies. Neurol Genet 2:e61.  Back to cited text no. 61
    
62.
Shamia A, Shaheen R, Sabbagh N, Almoisheer A, Halees A, Alkuraya FS (2015). Revisiting disease genes based on whole-exome sequencing in consanguineous populations. Hum Genet 134:1029–1034.  Back to cited text no. 62
    
63.
Torrelo A, Patel S, Colmenero I, Gurbindo D, Lendínez F, Hernández A, et al. (2010). Chronic atypical neutrophilicdermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. J Am Acad Dermatol 62:489–495.  Back to cited text no. 63
    
64.
Unger S, Lausch E, Rossi A, Mégarbané A, Sillence D, Alcausin M (2010). Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features. Am J Med Genet A 152A:2543–2549.  Back to cited text no. 64
    
65.
Vodopiutz J, Seidl R, Prayer D, Khan MI, Mayr JA, Streubel B, et al. (2015). WDR73 mutations cause infantile neurodegeneration and variable glomerular kidney disease. Hum Mutat 36:1021–1028.  Back to cited text no. 65
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Body
Newly described ...
Mysterious cases...
Mysterious syndr...
Conclusion
References
Article Tables

 Article Access Statistics
    Viewed3180    
    Printed468    
    Emailed1    
    PDF Downloaded367    
    Comments [Add]    

Recommend this journal