Clinical utility gene card: for incontinentia pigmenti
EUROPEAN JOURNAL OF HUMAN GENETICS(2019)
Abstract
The clinical diagnosis of IP is based on the presence of dermatological lesions that develop in four successive, sometimes overlapping, characteristic stages that start shortly after birth with an inflammatory vesicular rash (stage1), followed by verrucous lesions (stage2). The third stage is marked by the appearance of a skin area displaying hyperpigmentation that at the fourth stage becomes patches of atrophic hypopigmented skin. In addition, IP females have heterogeneous and often severe clinical signs including ophthalmological (strabismus, cataracts, optic atrophy, retinal vascular pigmentary abnormalities, microphthalmia), odontological, (partial anodontia, delayed dentition, cone/peg-shaped teeth, impactions) and neurological defects (seizures, spastic paralysis, motor, and mental retardation, microcephaly).1 IP is a genomic disorder inherited as an X-linked dominant trait. IP is generally lethal in males while heterozygous females survive owing to functional mosaicism.1 All cases of IP are due to mutations in NEMO (nuclear-factor-kappa-B essential modulator)/IKBKG gene located in Xq28 region, and the mutation detection rate in IP is around 80%. IKBKG, encodes the regulatory subunit of the IkB kinase complex required for nuclear factor-kB (NF-kB) activation.2, 3 Mutations in different domains of protein may produce different effects on NF-kB activation by reducing or abolishing the response after stimulations. Noteworthy, some IKBKG hypomorphic mutations, affecting the zinc finger (ZF) domain of the NEMO protein and reducing but do not eliminating NF-kB activation, were found in surviving male patients. These males are affected by a different disease, named hypohidrotic ectodermal dysplasia-associated with severe immunodeficiency (EDA-ID HED-ID OMIM#300291) or occasionally associated with osteopetrosis and lymphoedema (OL-EDA-ID).4, 5 The most frequent mutation in IP (70%) is a recurrent exon 4_10 deletion (NEMOexon4_10del) due to non allelic homologous recombination that occurs between two repeats (MER67B) located in intron 3 and downstream exon 10, causing the removal of the entire genomic region from exon4 to 10.6, 7 Missense, nonsense, deletions, and insertions have been reported in addition to gross rearrangements.8 With the exception of a tract of cytosines in exon 10 that appears to be prone to mutations in IP/HED-ID, no mutational hotspots or common point mutations are seen. To date, 53 different mutations (from large deletions to single amino-acid substitutions) affecting IKBKG have been reported: 7 gross deletions, 27 frameshift, 11 nonsense, four missense, one is an in-frame deletion of one codon, two are splice-site mutations, and one is a nonstop mutation.6, 7, 8 No evident genotype–phenotype correlation is apparent from comparison of patients with different loss-of-function mutations. The majority of mutations are ‘private’ to specific families. The rate of de novo mutations is about 65%. Comment: Predictive testing in IKBKG should be considered on an individual case basis only, as long as no preventive treatment is available. Long-range PCR: 100% (only heterozygous IKBKGexon 4_10 deletion). IKBKG sequencing:>80% (heterozigous for IKBKG point mutation). Quantitative PCR: 60% heterozygous IKBKG deletion. Comment: Quantitative PCR does not detect the point mutations in the gene nor other genomic alterations outside the IP locus. Depending on the technique and methods used in each laboratory, the sensitivity may vary. It is recommended to scan SNP data bases periodically, to check for the identification of novel SNPs, prone to interfere with primer hybridization (http://www.ncbi.nlm.nih.gov/). Long-range PCR: 100%, provided that the PCR specifically targets the IKBKG gene. IKBKG sequencing: >90%. The main concern is the occasional detection of exonic variants of uncertain significance, of which the responsibility for the disease is often difficult to demonstrate. Quantitative PCR: >90% for heterozygous IKBKG deletions. The clinical sensitivity depends on variable factors such as age or family history. Moreover, IP patients have heterogeneous clinical presentation. Indeed, while they have always-typical linear skin lesions (starting at birth and spontaneously evolving in four overlapping dermatological stages), they inconsistently exhibit ophthalmologic (strabismus, cataracts, optic atrophy, retinal vascular pigmentary abnormalities, microphthalmia), odontological (partial anodontia, delayed dentition, cone/peg-shaped teeth, impactions), and neurological defects (seizures, spastic paralysis, motor and mental retardation, microcephaly). The severity of these additional clinical signs is variable.1, 6, 15 Clinical specificity is around 100%. The only (rare) pitfall consists in detecting the PIKBKG deletion, erroneously interpreted as the IKBKG deletion. The clinical specificity can be dependent on variable factors such as age or family history. In most cases, a detailed clinical assessment and skin biopsy will have been performed before genetic testing; therefore, presence of typically skin alterations represents not only a prerequisite to start genetic testing but also for the interpretation of IKBKG variations of uncertain significance. On the basis of the studies of large pedigrees, most, if not all, patients appear to develop symptoms. Skin lesions are almost consistently found, tooth and eye anomalies are found in more than 50% cases, and a CNS involvement is present in 10–30% cases.1, 6, 15 For patients who are tested, and result positive for mutations, genetic counselling should be provided. Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered. Index case in that family had been tested: Undetermined. We estimate that it is close to 100%. Index case in that family had not been tested: Undetermined. We estimate that it is >95%. It is notewhorty to mention that there is a low level risk for somatic mutations in IKBKG that could cause IP-like skin features, escaping classical molecular diagnosis. Clinical diagnosis may include: nervous system exam for seizures, spastic paresis, motor and mental retardation, microcephaly, ocular defects, dental defects, hair defects, and nail defects taking a family pedigree and clinical assessment by a clinical geneticist or other physician familiar. Skin biopsy is painful and will not specify the underlying genetic defect. Identification of a IKBKG mutation allows carriers to make informed reproductive decisions, which take into account the risk of having an IP-affected child. A woman with a mutation may decrease her risk of having an IP child affected with IP by taking advantage of prenatal diagnosis oocyte donation, adoption, and so on. Preimplantation genetic diagnosis (PGD) is possible but particular technical difficulties exist for IP. If the test result is negative (please describe) Determining that a female patient is not a carrier can relieve the anxiety related to genetic risk and allow for confident family planning. Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (Please describe) Yes. It is advised to confirm IP carrier status in affected mother. Although there is no cure for IP, the diagnosis helps to follow appropriate physical, cognitive, and behavioural management of the affected individual. Yes, genetic testing is the gold standard for confirmation of the diagnosis and the mode of inheritance, helps to avoid unnecessary and invasive diagnostic procedures. It allows prognostic evaluations and is the prerequisite for prenatal testing, PGD, and genetic risk estimation of relatives. Molecular confirmation of the diagnosis will limit unnecessary further aetiological investigations, which can often be invasive and unpleasant. Many parents feel guilty, and may be relieved after a genetic diagnosis is obtained. Parents also find encouragement and support in dealing with daily anxieties and difficulties by becoming members of clubs and associations that welcome affected families. A molecular diagnosis enables a female carrier of mutation to make informed reproductive decisions. The authors declare no conflict of interest. This work was supported by Telethon (grant#GGP08125) to MVU and by Fondazione ‘Roma-Terzo Settore' to MVU. AP is supported by a Postdoctoral fellowship from the Association Incontinentia Pigmenti France (IPF). The authors wish to thank the patients, their families and patient associations: Italian I.P.ASS.I. Onlus (www.incontinentiapigmenti.it), the Incontinentia Pigmenti International Foundation (IPIF) (www.ipif.org), and the Incontinentia Pigmenti France (http://www.incontinentiapigmenti.fr).
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Key words
Health care,Neurological disorders,Biomedicine,general,Human Genetics,Bioinformatics,Gene Expression,Cytogenetics
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