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Compound heterozygote CDK5RAP2 mutations in a Guatemalan/Honduran child with autosomal recessive primary microcephaly, failure to thrive and speech delay

2015; Wiley; Volume: 167; Issue: 6 Linguagem: Inglês

10.1002/ajmg.a.36975

1552-4833

Mindy H. Li, Kelly Arndt, Soma Das, Elliott Mark Weiss, Yaning Wu, Kriti Gwal, Karuna Shekdar, Elaine H. Zackai,

Genomic variations and chromosomal abnormalities

Autosomal recessive primary microcephaly (MCPH) is a rare phenotype characterized by a occipitofrontal circumference (OFC) at birth measuring less than at least three standard deviations (SD) below the mean [Verloes et al.; Pagnamenta et al., 2012]. Individuals have reduced brain size, varied intellectual deficit without major cortical architecture abnormalities, absence of other organ malformations, and typically normal facial appearance aside from a sloping forehead that may accompany small cranial size [Issa et al., 2013a; Mahmood et al., 2011; Hassan et al., 2007; Woods et al., 2005; Issa et al., 2013b], which may help distinguish MCPH from other syndromic disorders associated with microcephaly. This disorder is genetically heterogeneous [Hassan et al., 2007] with at least 12 associated genes to date [Kaindl, 2014]. Initially, phenotypes were thought to be indistinguishable regardless of the causative gene, but later studies have suggested particular clinical features associated with different types of MCPH [Mahmood et al., 2011]. Mutations in the Cyclin-dependent protein kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) gene at the MCPH3 locus is one of the less common causes of MCPH, with only six families reported in the literature. CDK5RAP2 is thought to play a key role in cohesion and condensation of chromosomes during mitosis as the protein product localizes at the spindle poles [Issa et al., 2013b; 2013a; Bond et al., 2005; Mahmood et al., 2011; Kesavapany et al., 2004; Hassan et al., 2007; Megraw et al., 2011]. It is required for spindle check point regulation [Zhang et al., 2009] and is thought to potentially affect neuronal mitosis by disrupting the microtubules that are required for mitotic spindle assembly [Hassan et al., 2007; Mahmood et al., 2011]. CDK5RAP2 has also been shown to be expressed highly in the central nervous system in mouse and human studies [Issa et al., 2013a; Mahmood et al., 2011]. Previously reported individuals with mutations in CDK5RAP2 have a wide range of neurologic deficits (Supplementary Table I). This is the seventh report of an individual with MCPH who was found to have compound heterozygote mutations in CDK5RAP2, one novel and one previously reported. Informed consent was obtained from the patient's mother to participate in this report and allow publication of patient photographs and clinical information. The patient is a male who presented at six months of age due to failure to thrive requiring nasogastric tube feeding. There were no significant prenatal complications. He was born via spontaneous vaginal delivery at 40 weeks gestation to an 18-year-old G1P1 Honduran mother and a 24-year-old Guatemalan father. Family history was unremarkable, and parents were non-consanguineous. Birth weight was 3.2 kg (−0.3 SD), birth length was 47 cm (−1.5 SD), and birth occipito-frontal circumference (OFC) was 30.5 cm (−3.1 SD). Since birth the patient had poor growth, with OFC being disproportionately small (Supplemental Online Fig. 1A–D). A cranial MRI done at 4.5 months was limited due to patient motion, but grossly there were no major structural abnormalities. At six months old the patient's physical exam was notable for severe microcephaly with OFC at 35.5 cm (−6.4 SD), posterior plagiocephaly, sloping forehead, and upslanted palpebral fissures consistent with ethnicity (Fig. 1A). Development was appropriate for age; he was able to sit unsupported, pull to stand, reach for objects, recognize strangers, and babble. Cranial MRI done at six months showed severe microcephaly, small frontal lobes, abnormal corpus callosum with foreshortening, absent rostrum and blunted appearance of the splenium (Fig. 1C). Follow up exam at 13 months of age showed his OFC was 37.5 cm (−6.8 SD), and his development was appropriate for a 13 month old. He walked independently at ten months and was able to self-feed (though he continued to require nasogastric feedings for seven months due to poor weight gain), wave bye-bye, follow 1-step commands, and say 5–6 words. By 21 months his OFC was 39 cm (−6.6 SD). His motor skills were appropriate for age, but his vocabulary had not progressed. Evaluation through early intervention services identified expressive speech delay requiring speech therapy. Evaluation by a developmental pediatrician was recommended to the family but was not completed. A heart murmur noted at 21 months of age was evaluated by cardiology as benign, and echocardiogram and electrocardiogram were normal. Sequence analysis of CDK5RAP2 showed two predicted truncating nonsense mutations: 1) NM_018249.5: c.4441C>T (p.Arg1481*) in exon 30 predicting protein truncation by 412 amino acids, first reported by Issa et al., [2013b] and 2) NM_018249.5: c.5227C>T (p.Gln1743*) in exon 34 predicting protein truncation by 150 amino acids, which has not been reported previously (Fig. 2A–B). Additional testing included a single nucleotide polymorphism (SNP) array (Ilumina HumanOmni1-Quad BeadChip), which did not identify pathogenic deletions or duplications. High density array Comparative Genomic Hybridization (array-CGH) assay (custom Agilent 4 × 180) of the following genes also did not show evidence of deletions or duplications: ASPM, ARFGEF2, CDK5RAP2, CEP63, CEP152, CENPJ, MED17, MCPH1, NDE1, PNKP, STIL, SLC25A19, and WDR62. The phenotypic spectrum of patients with MCPH is broad, and aside from the presence of congenital microcephaly and absence of other organ malformations, clinical findings may vary [Verloes et al., 2009; Mahmood et al., 2011]. CDK5RAP2 is one of the more rare causes of MCPH with six mutations across six families reported prior in the literature. Supplementary Table I outlines all known reported patients and clinical phenotypes in detail, and Fig. 2C shows the locations of mutations in CDK5RAP2 that have been described. The first patients were described in two consanguineous Northern Pakistani families [Bond et al., 2005]. All affected individuals had congenital microcephaly and varying degrees of intellectual deficit. A third Northern Pakistani consanguineous family with similar phenotype was reported by [Hassan et al., 2007], and the nonsense mutation reported (c.246T>A, p.Y82*) was also described by [Bond et al., 2005]. Additional patients have since been reported in a consanguineous Somali family identified by [Pagnamenta et al., 2012], a Caucasian/Cherokee female [Tan et al., 2014], and two Italian brothers [Issa et al., 2013b] as well as the individual described here. The range of growth restriction has varied among the reported families. Every affected individual has congenital microcephaly by definition, but birth weight ranges from low [Pagnamenta et al., 2012; Bond et al., 2005] to normal. The child reported here had normal birth weight (38th centile, Supplemental Online Fig. 1B), but by three months weight gain was so poor he required nasogastric feedings. However, Family 2 reported by Bond et al., 2005 had normal growth after birth. Reported length/height has also varied from low [Tan et al., 2014; Pagnamenta et al., 2012; Issa et al., 2013b] to normal. The child reported here started with lower birth length (10th centile, Supplemental Online Fig. 1C) but eventually also fell off the growth curve by 6 months. Conversely, Patient 1 reported by Issa et al., [2013b] was below 10th centile in length at 3 months, but this improved to average stature by 9 years of age. Findings suggest accurate longitudinal growth predictions are difficult to make in patients with MCPH caused by CDK5RAP2 mutations. From a development standpoint most affected individuals are reported to have normal gross motor skills, but all have some degree of cognitive delay and varied ages at presentation. Patient VI:7 reported by Bond et al., [2005] had worsened cognitive functioning as a teenager than as a child. The individual reported here met early cognitive and motor developmental milestones, but by 21 months was diagnosed with mild speech delay. Intelligence testing performed on a number of reported patients with MCPH caused by CDK5RAP2 mutations (Supplementary Table I) further supports the spectrum of developmental delay that can be seen. Caution must be taken when counseling families regarding outcomes given this variability. In summary, we present the first patient of Hispanic descent with MCPH with compound heterozygote mutations in CDK5RAP2, including a novel pathogenic nonsense mutation. This patient highlights the clinical relevance of CDK5RAP2 and demonstrates the variability present in patients with CDK5RAP2 mutations from both a growth and development standpoint, which should be taken into consideration during prognostic discussions with affected patients and their families. The authors acknowledge the patient and his family for their agreement to participate in this report. 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