Neurobiology of Aging xxx (2016) 1e5

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Novel PSEN1 mutations (H214N and R220P) associated with familial Alzheimer’s disease identified by targeted exome sequencing Elena Piccoli a,1, Giacomina Rossi a, *,1, Tommaso Rossi b, Giuseppe Pelliccioni b, Ilaria D’Amato a, Fabrizio Tagliavini a, Giuseppe Di Fede a a b

Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy Division of Neurology, Geriatric Hospital, INRCA IRCCS, Ancona, Italy

a r t i c l e i n f o

a b s t r a c t

Article history: Received 10 November 2015 Received in revised form 30 December 2015 Accepted 30 January 2016

Autosomal dominant Alzheimer’s disease (AD) is caused by mutations in amyloid precursor protein, presenilin 1 (PSEN1), and presenilin 2 genes and is mostly associated with early-onset form of AD (EOAD), whereas very few mutations were also found in late-onset AD (LOAD) cases. Because of the clinical overlapping between AD and other degenerative dementias such as frontotemporal dementias, a widespectrum genetic analysis should be envisaged in the differential diagnosis of this group of disorders. We used next-generation sequencing techniques to analyze 10 genes involved in dementia on a cohort of 20 EOAD and 20 LOAD cases. We found 5 rare coding variants (frequency Aac H214N

73659462 44067289

NM_000021.3:c.659G>C cGa>cCa R220P NM_001123066.3:c.1228C>T Ctt>Ttt L410Fa

44071317 42429809

NM_001123066.3:c.1535C>A cCc>cAc P512Hb NM_002087.2:c.1514C>G gCc>gGc A505 G

novel

SIFT PolyPhen ExAC No of Other previously freq % patients reported coding variants at the same codon del

prob dam 0

1

H214D (path); H214Y (path)

novel tol rs199759929 tol

prob dam 0 prob dam 0.01

1 1

none none

rs192236920 tol novel tol

prob dam 0.01 benign 0.01

1 1

P512S (ExAc Freq % ¼ 0.1) none

Key: dam, damaging; del, deleterious; ExAc, Exome Aggregation Consortium browser; path, pathogenic; prob, probably; tol, tolerated. (http://exac.broadinstitute.org). a in exon 6. b in exon 8.

at 82 years. Her 53-year-old brother (II-3) and her two 45- and 41-year-old sons (III-1 and III-2) were healthy. She was referred to the Neurology Unit of INRCA Geriatric Hospital in Ancona for a 1-year history of depression and apathy,

followed in few months by attention deficits, impairment of anterograde memory, spatial and temporal orientation deficits, and aberrant motor behavior. On admission in hospital, neurologic examination revealed important deficits in judgment, poor awareness

Fig. 1. Pedigrees of the AD cases carrying a PSEN1 mutation. (A) Pedigree of the EOAD case with PSEN1 H214N mutation and (B) the sequencing chromatogram. (C) Pedigree of the LOAD case with PSEN1 R220P mutation and (D) the sequencing chromatogram. The probands are marked by arrows, black symbols denote affected members, white symbols denote unaffected members. (E) Alignment between PSEN1 and PSEN2 amino acid sequences showing the PSEN1 H214/PSEN2 H220 codon conservation and the lack of conservation of PSEN1 R220 in PSEN2. Abbreviations: AD, Alzheimer’s disease; EOAD, early-onset AD; LOAD, late-onset AD; PSEN, presenilin. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

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E. Piccoli et al. / Neurobiology of Aging xxx (2016) 1e5

of her cognitive disturbances, perseveration, anxiety, slight ataxic gait and psychomotor slowing-down. General physical examination was normal. Laboratory tests on blood and urine, including B12 vitamin, folate and thyroid function tests, and abdominal echography and chest X-ray were unremarkable. Neuropsychological assessment showed a severe multi-domain cognitive impairment, mainly involving verbal and spatial memory, temporal and spatial orientation, praxias, comprehension, writing. Mini-mental state examination score was 6.8/30. Brain magnetic resonance imaging showed diffuse corticosubcortical cerebral atrophy and multiple gliotic foci in the deep white matter of left parietal lobe and both semi-oval centers. EEG showed defects in the organization of the background electric brain activity associated with diffuse recurrent symmetrical sharp waves. Cerebrospinal fluid Ab1-42 level was 332 pg/mL (control values >500), total tau value was 400 pg/mL (control values