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REVIEW ARTICLE |
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Year : 2018 | Volume
: 7
| Issue : 1 | Page : 1-6 |
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Clinical genetics revisited: effect of new techniques (next-generation sequencing, comparative genomic hybridization) on previous diagnoses
Andre Megarbane MD, PhD
Institut Jerome Lejeune, Centre de Ressources Biologiques BioJeL, Paris, France
Date of Submission | 24-Nov-2017 |
Date of Acceptance | 01-Dec-2017 |
Date of Web Publication | 26-Mar-2018 |
Correspondence Address: Andre Megarbane Institut Jerome Lejeune, 75015 Paris France
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/MXE.MXE_3_17
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 |
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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.
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 | | |
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].
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 | | |
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
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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 | | |
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].
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 | | |
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.
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[Table 1], [Table 2], [Table 3], [Table 4]
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