Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.
Child Neurology and Psychiatry Unit, Department of Neuroscience, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy.
Genes (Basel). 2023 Jan 17;14(2):245. doi: 10.3390/genes14020245.
Neuronal ceroid lipofuscinoses (CNL) are lysosomal storage diseases that represent the most common cause of dementia in children. To date, 13 autosomal recessive (AR) and 1 autosomal dominant (AD) gene have been characterized. Biallelic variants in cause CLN7 type, with nearly 50 pathogenic variants, mainly truncating and missense, reported so far. Splice site variants require functional validation. We detected a novel homozygous non-canonical splice-site variant in in a 5-year-old girl who presented with progressive neurocognitive impairment and microcephaly. The diagnostic procedure was elicited by clinical genetics first, and then confirmed by cDNA sequencing and brain imaging. Inferred by the common geographic origin of the parents, an autosomal recessive inheritance was hypothesized, and SNP-array was performed as the first-line genetic test. Only three AR genes lying within the observed 24 Mb regions of homozygosity were consistent with the clinical phenotype, including , and . The cerebral and cerebellar atrophy detected in the meantime by MRI, along with the suspicion of accumulation of ceroid lipopigment in neurons, prompted us to perform targeted sequencing. Following the detection of a splice site variant of uncertain significance, skipping of exon 8 was demonstrated by cDNA sequencing, and the variant was redefined as pathogenic.
神经元蜡样脂褐质沉积症（CNL）是溶酶体贮积病，是儿童痴呆的最常见原因。迄今为止，已经鉴定了 13 种常染色体隐性（AR）和 1 种常染色体显性（AD）基因。 中的双等位基因变异导致 CLN7 型，迄今为止已报道了近 50 种致病性变异，主要是截断和错义。剪接位点变异需要功能验证。我们在一名 5 岁女孩中检测到了一种新型纯合非典型剪接位点变异，该女孩表现为进行性神经认知障碍和小头畸形。首先通过临床遗传学引出诊断程序，然后通过 cDNA 测序和脑成像进行确认。根据父母的共同地理起源，假设为常染色体隐性遗传，并进行 SNP 芯片作为一线遗传检测。只有三个位于观察到的 24 Mb 纯合区域内的 AR 基因与临床表型一致，包括 、 和 。同时通过 MRI 检测到大脑和小脑萎缩，以及神经元中类蜡脂褐素积累的怀疑，促使我们进行靶向测序。在检测到不确定意义的剪接位点变异后，通过 cDNA 测序证明了外显子 8 的跳跃，该变异被重新定义为致病性。
