Mosaic Deletion of the NF1 Gene in a Patient With Cognitive Disability and Dysmorphic Features But Without Diagnostic Features of NF1

Abstract

We report on an 18-year-old man who vividly illustrates the diagnostic conundrums new genetic testing technology can generate. Following referral to clinical genetics, microarray analysis identified a de novo 2.8 Mb deletion on chromosome 17q11.2, including the entire NF1 gene, yet he does not meet diagnostic criteria for neurofibromatosis type 1 (NF1). To our knowledge this is the first reported case of a patient with an NF1 gene deletion, ascertained unexpectedly with no family history and without diagnostic features.Our patient has severe global developmental delay, autism, epilepsy, dysmorphic features ( Fig. 1), a kyphoscoliosis, chronic microscopic hematuria, a shorter left leg and histologically confirmed facial hemangiomas. He is the third child of healthy unrelated parents (maternal and paternal ages 28 and 32 years at birth, respectively). His mother became concerned about his development from the age of 8 months. He started walking at 23 months and had grommets inserted age 2 years. Griffiths developmental scale results at 29.5 months were: Locomotor 20 months; Personal and Social Skills 18 months; Hearing and Speech 20 months; Eye Hand Coordination 22 months; Performance-did not cooperate. He attended a special needs school from the age of 3 years. He currently has a small vocabulary, can repeat sentences he has heard and is able to answer simple questions. At the age of 7 years he was diagnosed with autistic spectrum disorder. At age 15 years he developed generalized tonic-clonic seizures that were well controlled with carbamazepine. EEG showed generalized slowing consistent with nonspecific cerebral dysfunction, with more significant slowing over the right posterior tempero-occipital region, consistent with a focal nonspecific abnormality. CT head showed a possible small lesion on the left side of the brain that was difficult to interpret because of movement. A brain MRI scan done at the age of 5 years had been normal.From the age of 7 years he was diagnosed with a mild stable kyphoscoliosis. He wears an insert in his shoe to compensate for a slightly (1 cm) shorter left leg. He has had chronic microscopic hematuria, first detected at the age of 4 months; renal tract ultrasound scan was normal (last done age 17 years) as were blood pressure and renal function (now monitored annually). His mother also has persistent microscopic hematuria; this is thought to most likely represent autosomal dominant thin basement membrane disease. Around the age of 13 years he developed several angiomatous lesions on his face. Histology of a left eyebrow lesion confirmed this to be a hemangioma. Growth parameters were normal (weight 50th-75th, height 75th, and OFC 91st-98th centiles when last seen age 18 years).Following the surprising microarray results which identified a de novo 2.8 Mb deletion on chromosome 17q11.2, including the entire NF1 gene (Fig. 2), further review confirmed the absence of cardinal features of NF1: with no caf e-au-lait spots, neurofibromata, skin flexure freckling or optic gliomas. He has not ...

Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy

“…45 . In HGMD, there is no NF1 variant primarily associated with an epilepsy syndrome except for a 2.8 Mb mosaic deletion encompassing NF1 and many other genes 46 . Our result indicates that damaging NF1 variants can be an often overlooked but relatively frequent cause of EE/DEE, especially of infantile spasm.…”

Emerging genotype–phenotype relationships in patients with large NF1 deletions

“…It has been estimated that 8–10% of all large NF1 deletions are atypical (Pasmant et al 2010; Messiaen et al 2011). Atypical NF1 deletions may occur as germline mutations but can also be of postzygotic origin and hence may be associated with somatic mosaicism with normal cells (Taylor Tavares et al 2013; Vogt et al 2014). Atypical NF1 deletions are not only highly heterogeneous in terms of their length but also in terms of their underlying mutational mechanisms which may involve aberrant DNA double strand break repair and/or replication and retrotransposon-mediated mechanisms (Vogt et al 2014 and references therein).…”

Classification of NF1 microdeletions and its importance for establishing genotype/phenotype correlations in patients with NF1 microdeletions

“…Mosaicism with normal cells has been shown to influence the clinical phenotype in patients with NF1 microdeletions, often leading to a mild manifestation of the disease (Kehrer-Sawatzki et al 2012 ; Taylor Tovares et al 2013 ). Hence the accurate classification of the type of NF1 microdeletion by methods such as microarray analysis may also help to identify patients with a high probability of being mosaic which might then require analysis of tissues other than blood in order to confirm or exclude mosaicism (Table 4 ).…”

“…Approximately 8–10% of all NF1 microdeletions are considered to be atypical (Pasmant et al 2010 ; Messiaen et al 2011 ). They may occur as germline deletions but can also be of postzygotic origin and hence may be associated with somatic mosaicism with normal cells (Taylor Tovares et al 2013 ). It has been estimated that 59% of atypical NF1 deletions are of postzygotic origin and thus represent mosaic deletions (Vogt et al 2014 ).…”