Introduction 1 2 3 4 6 7 12 13 14 15 16 10 10 17 20 21 22 6 23 25 26 27 Genetics in hydrocephalus 28 30 10 20 31 32 10 15 20 32 43 44 45 L1CAM 46 47 11 48 49 50 51 59 59 64 65 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 79 84 85 86 87 88 89 90 1 Table 1 Summary of current known loci (or mutants) of hydrocephalus in vertebrates Species Strain Clinical form Trait* Locus Chromosome Human syntenic region Human Gene References Human  C AR Unknown unknown   10 15 27 32 43 Human  C AD Unknown 8q12.2–21.2 or unknown    44 45 Human  AO AD NPH unknown   50 Human  C X-linked L1cam X X L1CAM 46 Human  AO X-linked Unknown X X  49 Rat HTX C QTL D9Rat2  9q38  5q21.1, 18p11.22–31   65 68 Rat HTX C QTL D10Rat136, D10Rat135 10q32.1–10q32.3 17q21.3–q25.3  65 68 Rat HTX C QTL D11Arb2, D11Rat46 11q23 3q27–28, 22q11.21,10p12.2   65 68 Rat HTX C QTL D17Mit4, D17Rat154 17q12.1  1q43, 10p11.21–p13   65 68 Rat LEW/Jms C AR, (QTL) unknown unknown   70 71 Mouse C57BL/6J C QTL Vent8a 8 8p11–23, 13q11–34  72 Mouse C57BL/6J C QTL Vent4b 4 6p, 9  72 Mouse C57BL/6J C QTL Vent7c 7 19q10–13  72 Mouse hy1 C AR unknown unknown   73 74 Mouse hy2 C AR unknown unknown   75 76 Mouse hy3 C AR Hydin 8 16q22.2 HYDIN 79 82 Mouse C57BL/10J C AR hyh 7 19q13.3 a-SNAP 87 100 Mouse C57BL6/J C AD Rfx4 10 12q24 RFX4 83 Mouse BALB/cHeA C AR hhy 12 14q32  88 Mouse ch C AR Mf1 13 6p25 FREAC-3 84 Mouse STOCK tb C AR oh unknown   77 78 Mouse C57BL/6*CBA/J C AR Mdnah5 15 5p15.2 DNAH5 106 Mouse C57BL/CBA C AD Otx2 14 14q21-q22 OTX2 122 Mouse 129P2/OlaHsd C AR Msx1 5 4p16.3-p16.1 MSX1 107 108 Mouse C57BL/6 C AR Socs7 11 17q12 SOCS7 118 Mouse C57BL/6J C AR Nmhc-b 11 17q13 MYH10 121 Zebrafish m404/m491 C AR apo unknown   89 90 Zebrafish m409/m432 C AR cudak unknown   89 90 Zebrafish m691 C AR eagle unknown   89 90 Zebrafish m591 C AR endeavor unknown   89 90 Zebrafish m584 C AR enterprise unknown   89 90 Zebrafish m492/m510 C AR galileo unknown   89 90 Zebrafish m445/m585/m700 C AR gumowy unknown   89 90 Zebrafish m727 C AR hubble unknown   89 90 Zebrafish m221/m470/m680 C AR interrail unknown   89 90 Zebrafish m733 C AR kepler unknown   89 90 Zebrafish m728 C AR neil unknown   89 90 Zebrafish m481 C AR pan twardowski unknown   89 90 Zebrafish m172/m476 C AR uchu hikoushi unknown   89 90 Zebrafish m766 C AR voyager unknown   89 90 Zebrafish m331 C AR viking unknown   89 90 Zebrafish m479/m627 C AR yura unknown   89 90 Zebrafish m111/m307/m512/m97 C AR zezem unknown   89 90 * Genetic trait, AR: autosomal recessive, AD:autosomal dominant, QTL: Quantitative trait locus, ** clinicalform, C: congenital, AO: Adut-Onset Developmental, physiological and anatomical pathology of hydrocephalus 61 91 64 92 93 94 95 96 97 98 98 In summary, the pathological studies of hydrocephalus clearly indicate that impaired and abnormal brain development in the early development stage caused by altered neural cell fate and perturbed regulation of cellular proliferation and apoptosis. The abnormal brain development subsequently leads to the accumulation of the CSF in cerebral cavities. All these cellular and developmental events eventually lead to the congenital hydrocephalus accompanied by possible secondary inflammatory reaction and neurovascular pathogenesis. The molecular and cellular etiology of hydrocephalus 99 100 87 100 101 102 105 81 82 106 107 108 84 83 83 109 110 111 112 113 114 110 115 116 117 118 119 120 121 122 1 123 Fig. 1 A, D, G B, E, H C, F, I 123  Future prospects It is essential to recognize that molecular genetics is the only current scientific approach that can be used to study hydrocephalus in which the usual concern about whether an observed phenomenon is a consequence or a cause is completely addressed. Despite our knowledge of the genetics of hydrocephalus in animal models, we have very limited knowledge about the genetic and molecular mechanisms that cause human hydrocephalus. Without this knowledge, it is impossible to say whether the pathogenesis of human hydrocephalus is comparable to that seen in animal models, and impractical to extrapolate data gained from animal models to humans. In order to better understand human hydrocephalus and to develop more appropriate translational research, it will be necessary to conduct large-scale genetic studies of human hydrocephalus. If, and when, more heritable forms of human hydrocephalus are identified, and underlying genes and their functions are characterized, then this knowledge could be used to improve patient care in a variety of different ways such as prenatal diagnosis and new potential therapeutic approaches. Possible new mechanisms other than altered CSF circulation and resorption, if uncovered via the genetic research, may also help explain why patients with hydrocephalus may experience symptomatic progression despite functioning shunts. Efforts to identify genetic variants associated with susceptibility to genetic diseases rely on three major approaches: pedigree and sib-pair linkage analysis and population association studies. The differences among these study designs reflect their derivation from biological versus epidemiological traits. Like most common diseases, it would be very difficult to identify and recruit large pedigrees in hydrocephalus that show hereditary transmission of the condition. Therefore, the last two approaches, sib-pair linkage analysis and population association studies, are the best options for the genetic study on this disease. For any study, but particularly in the case of genetic mapping for a common disease, a large sample size is crucial in achieving statistical significance. Recent advances in the genomics and statistical methodology in genetic mapping will certainly help in making well-powered studies more feasible, by reducing the number of genetic markers or workload required for these studies. For example, since many genes and loci response for hydrocephalus in animal models have been mapped, candidate genes approach will certainly be the very first choice to test the collected human hydrocephalus population for linkage and association analysis. In collaboration with the Hydrocephalus Association (HA), our group has initiated a genetic study of human hydrocephalus. As part of a prospective study that has been approved by the Johns Hopkins Institutional Review Board, we are collecting blood samples from both congenital and acquired NPH hydrocephalus patients. The objectives of this study are to identify the genetic loci responsible for the development of hydrocephalus, to examine the relationship between genotype and phenotype and to define the functions of these genes during early development. This is the first large-scale research study of its kind and information gained from this study will undoubtedly provide invaluable information concerning the developmental mechanisms of this disease in humans. Such knowledge will hopefully lead to the more reasonable treatment schemes, the better diagnostic tools, and the more effective therapeutic modalities.