from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.units import cm, mm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, KeepTogether
)
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.graphics.shapes import Drawing, Rect, String, Line, Circle, Polygon, Ellipse
from reportlab.graphics import renderPDF
from reportlab.platypus.flowables import Flowable
import math

# ─── Colors ──────────────────────────────────────────────────────────────────
C_BG        = colors.HexColor("#F0F4FF")
C_HDR       = colors.HexColor("#1A237E")   # dark indigo
C_HDR_LIGHT = colors.HexColor("#3949AB")   # medium indigo
C_ACCENT    = colors.HexColor("#E53935")   # red
C_YELLOW    = colors.HexColor("#FFF9C4")   # pale yellow
C_GREEN     = colors.HexColor("#E8F5E9")   # pale green
C_BLUE      = colors.HexColor("#E3F2FD")   # pale blue
C_PURPLE    = colors.HexColor("#F3E5F5")   # pale purple
C_ORANGE    = colors.HexColor("#FFF3E0")   # pale orange
C_WHITE     = colors.white
C_TEXT      = colors.HexColor("#212121")
C_BOX_HDR  = colors.HexColor("#5C6BC0")   # box header indigo
C_TEAL      = colors.HexColor("#006064")

# ─── Document Setup ──────────────────────────────────────────────────────────
doc = SimpleDocTemplate(
    "/tmp/workspace/genetics-notes/Genetics_Short_Notes.pdf",
    pagesize=A4,
    leftMargin=1.5*cm, rightMargin=1.5*cm,
    topMargin=1.5*cm, bottomMargin=1.5*cm
)

W, H = A4
CW = W - 3*cm   # content width

# ─── Styles ──────────────────────────────────────────────────────────────────
styles = getSampleStyleSheet()

def S(name, **kw):
    return ParagraphStyle(name, **kw)

TITLE_STYLE = S("Title2",
    fontSize=26, leading=32, textColor=C_WHITE,
    fontName="Helvetica-Bold", alignment=TA_CENTER)

UNIT_STYLE = S("Unit",
    fontSize=18, leading=24, textColor=C_WHITE,
    fontName="Helvetica-Bold", alignment=TA_LEFT)

HEADING_STYLE = S("H2",
    fontSize=15, leading=20, textColor=C_HDR,
    fontName="Helvetica-Bold", alignment=TA_LEFT,
    spaceAfter=4)

SUBHD_STYLE = S("SubH",
    fontSize=13, leading=18, textColor=C_HDR_LIGHT,
    fontName="Helvetica-Bold", alignment=TA_LEFT,
    spaceAfter=2)

BODY_STYLE = S("Body2",
    fontSize=12, leading=17, textColor=C_TEXT,
    fontName="Helvetica", alignment=TA_JUSTIFY,
    spaceAfter=3)

BULLET_STYLE = S("Bullet2",
    fontSize=12, leading=16, textColor=C_TEXT,
    fontName="Helvetica", leftIndent=12, bulletIndent=0,
    spaceAfter=3)

SMALL_STYLE = S("Small2",
    fontSize=10, leading=14, textColor=colors.HexColor("#424242"),
    fontName="Helvetica", alignment=TA_LEFT)

NOTE_STYLE = S("Note",
    fontSize=11, leading=15, textColor=C_ACCENT,
    fontName="Helvetica-Bold", alignment=TA_LEFT)

# ─── Helper Flowables ────────────────────────────────────────────────────────

class ColorBox(Flowable):
    """Colored background banner."""
    def __init__(self, text, style, bg, width, height=32, radius=6):
        super().__init__()
        self.text = text
        self.style = style
        self.bg = bg
        self.bw = width
        self.bh = height
        self.radius = radius
    def wrap(self, *args):
        return self.bw, self.bh
    def draw(self):
        self.canv.setFillColor(self.bg)
        self.canv.roundRect(0, 0, self.bw, self.bh, self.radius, fill=1, stroke=0)
        p = Paragraph(self.text, self.style)
        p.wrapOn(self.canv, self.bw - 16, self.bh)
        p.drawOn(self.canv, 8, (self.bh - p.height) / 2)


def unit_header(title, subtitle=""):
    items = [
        ColorBox(title, UNIT_STYLE, C_HDR, CW, height=44, radius=8),
    ]
    if subtitle:
        items.append(Spacer(1, 4))
        items.append(Paragraph(subtitle, SMALL_STYLE))
    items.append(Spacer(1, 6))
    return items


def section_box(title, content_rows, bg=C_BLUE):
    """Bordered box with a header and bullet rows."""
    data = [[Paragraph(f"<b>{title}</b>", SUBHD_STYLE)]] + \
           [[Paragraph(r, BODY_STYLE)] for r in content_rows]
    t = Table(data, colWidths=[CW])
    t.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,0), C_BOX_HDR),
        ('TEXTCOLOR',  (0,0), (-1,0), C_WHITE),
        ('BACKGROUND', (0,1), (-1,-1), bg),
        ('BOX',        (0,0), (-1,-1), 1, C_HDR_LIGHT),
        ('LINEBELOW',  (0,0), (-1,0), 1, C_WHITE),
        ('TOPPADDING',    (0,0), (-1,-1), 6),
        ('BOTTOMPADDING', (0,0), (-1,-1), 6),
        ('LEFTPADDING',   (0,0), (-1,-1), 10),
        ('RIGHTPADDING',  (0,0), (-1,-1), 10),
        ('ROUNDEDCORNERS', [6]),
    ]))
    return [t, Spacer(1, 8)]


def two_col_table(rows, bg1=C_YELLOW, bg2=C_GREEN):
    """Two-column key-value table."""
    data = [[Paragraph(f"<b>{k}</b>", SUBHD_STYLE),
             Paragraph(v, BODY_STYLE)] for k,v in rows]
    t = Table(data, colWidths=[CW*0.35, CW*0.65])
    t.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (0,-1), bg1),
        ('BACKGROUND', (1,0), (1,-1), bg2),
        ('BOX',        (0,0), (-1,-1), 1, C_HDR_LIGHT),
        ('INNERGRID',  (0,0), (-1,-1), 0.5, colors.HexColor("#9FA8DA")),
        ('TOPPADDING',    (0,0), (-1,-1), 6),
        ('BOTTOMPADDING', (0,0), (-1,-1), 6),
        ('LEFTPADDING',   (0,0), (-1,-1), 8),
        ('VALIGN',     (0,0), (-1,-1), 'MIDDLE'),
    ]))
    return [t, Spacer(1, 8)]


def hr():
    return [HRFlowable(width=CW, thickness=1.5, color=C_HDR_LIGHT), Spacer(1, 6)]


# ═══════════════════════════════════════════════════════════════════════════════
#  DIAGRAMS (pure ReportLab Drawing)
# ═══════════════════════════════════════════════════════════════════════════════

# ── Diagram 1: Gene Structure ─────────────────────────────────────────────────
def gene_structure_diagram():
    d = Drawing(CW, 130)
    # background
    d.add(Rect(0, 0, CW, 130, fillColor=colors.HexColor("#E8EAF6"), strokeColor=None))

    # title
    d.add(String(CW/2, 113, "GENE STRUCTURE", fontSize=12,
                 fontName="Helvetica-Bold", fillColor=C_HDR, textAnchor="middle"))

    # DNA double helix simplified as two parallel wavy lines
    import math
    cx = CW / 2
    # Draw chromosome bar
    d.add(Rect(20, 68, CW-40, 18, fillColor=colors.HexColor("#3949AB"),
               strokeColor=C_HDR, strokeWidth=1))
    d.add(String(cx, 73, "CHROMOSOME", fontSize=9,
                 fontName="Helvetica-Bold", fillColor=C_WHITE, textAnchor="middle"))

    # Gene segments on chromosome
    gene_data = [
        (30,  "Promoter",  colors.HexColor("#FF7043")),
        (100, "Exon 1",    colors.HexColor("#66BB6A")),
        (170, "Intron",    colors.HexColor("#FFCA28")),
        (240, "Exon 2",    colors.HexColor("#66BB6A")),
        (310, "3'UTR",     colors.HexColor("#AB47BC")),
    ]
    for x, label, col in gene_data:
        bw = 60
        d.add(Rect(x, 68, bw, 18, fillColor=col, strokeColor=C_WHITE, strokeWidth=0.8))
        d.add(String(x+bw/2, 73, label, fontSize=7,
                     fontName="Helvetica-Bold", fillColor=C_WHITE, textAnchor="middle"))

    # Arrow below
    d.add(Line(20, 55, CW-20, 55, strokeColor=C_HDR, strokeWidth=1.5))
    d.add(Polygon([CW-20, 55, CW-28, 58, CW-28, 52],
                  fillColor=C_HDR, strokeColor=C_HDR))
    d.add(String(cx, 44, "5' ─────────────────────── 3'", fontSize=9,
                 fontName="Helvetica", fillColor=C_HDR, textAnchor="middle"))

    # Labels below
    d.add(String(20, 28, "DNA is made of nucleotides:  Adenine (A)  |  Thymine (T)  |  Guanine (G)  |  Cytosine (C)",
                 fontSize=8, fontName="Helvetica", fillColor=C_TEXT))
    d.add(String(20, 14, "Gene = segment of DNA that codes for a specific protein",
                 fontSize=8, fontName="Helvetica-Bold", fillColor=C_ACCENT))
    return d


# ── Diagram 2: Chromosomal Aberrations ───────────────────────────────────────
def chromosomal_aberration_diagram():
    d = Drawing(CW, 155)
    d.add(Rect(0, 0, CW, 155, fillColor=colors.HexColor("#E8F5E9"), strokeColor=None))
    d.add(String(CW/2, 140, "CHROMOSOMAL ABERRATIONS", fontSize=12,
                 fontName="Helvetica-Bold", fillColor=C_HDR, textAnchor="middle"))

    types = [
        ("Deletion",   colors.HexColor("#EF5350"), "Loss of segment"),
        ("Duplication",colors.HexColor("#42A5F5"), "Extra copy"),
        ("Inversion",  colors.HexColor("#AB47BC"), "Segment reversed"),
        ("Translocation",colors.HexColor("#FFA726"),"Segment moves"),
    ]
    per_col = CW / 4
    for i, (name, col, desc) in enumerate(types):
        bx = i * per_col + 10
        # normal chr
        d.add(Rect(bx, 90, per_col-20, 38, fillColor=col,
                   strokeColor=C_HDR, strokeWidth=1, rx=10, ry=10))
        d.add(String(bx+(per_col-20)/2, 105, name, fontSize=8,
                     fontName="Helvetica-Bold", fillColor=C_WHITE, textAnchor="middle"))
        # arrow
        ax = bx+(per_col-20)/2
        d.add(Line(ax, 87, ax, 78, strokeColor=C_TEXT, strokeWidth=1))
        d.add(Polygon([ax, 76, ax-4, 81, ax+4, 81],
                      fillColor=C_TEXT, strokeColor=C_TEXT))
        # desc
        d.add(String(bx+(per_col-20)/2, 62, desc, fontSize=7,
                     fontName="Helvetica", fillColor=C_TEXT, textAnchor="middle"))

    d.add(String(CW/2, 42,
                 "Numerical: Aneuploidy (extra/missing chromosome)  |  Polyploidy (extra full set)",
                 fontSize=8, fontName="Helvetica-Bold", fillColor=C_ACCENT, textAnchor="middle"))
    d.add(String(CW/2, 28,
                 "Structural: Deletion, Duplication, Inversion, Translocation",
                 fontSize=8, fontName="Helvetica", fillColor=C_TEXT, textAnchor="middle"))
    d.add(String(CW/2, 14,
                 "e.g. Trisomy 21 = Down Syndrome (extra chr 21)",
                 fontSize=8, fontName="Helvetica-Bold", fillColor=C_HDR, textAnchor="middle"))
    return d


# ── Diagram 3: Patterns of Inheritance ───────────────────────────────────────
def inheritance_diagram():
    d = Drawing(CW, 200)
    d.add(Rect(0, 0, CW, 200, fillColor=colors.HexColor("#F3E5F5"), strokeColor=None))
    d.add(String(CW/2, 185, "AUTOSOMAL DOMINANT INHERITANCE (Pedigree)", fontSize=11,
                 fontName="Helvetica-Bold", fillColor=C_HDR, textAnchor="middle"))

    # Generation I - parents
    # Father (circle = female, square = male)
    # squares = males, circles = females
    def draw_male(cx, cy, affected=False):
        col = colors.HexColor("#1565C0") if affected else colors.HexColor("#90CAF9")
        d.add(Rect(cx-16, cy-16, 32, 32, fillColor=col,
                   strokeColor=C_HDR, strokeWidth=1.5))

    def draw_female(cx, cy, affected=False):
        col = colors.HexColor("#C62828") if affected else colors.HexColor("#FFCDD2")
        d.add(Circle(cx, cy, 16, fillColor=col,
                     strokeColor=C_ACCENT, strokeWidth=1.5))

    def couple_line(x1, y1, x2, y2):
        d.add(Line(x1, y1, x2, y2, strokeColor=C_TEXT, strokeWidth=1.5))

    def descent_line(px, py, cx, cy):
        mid_y = (py + cy) / 2
        d.add(Line(px, py, px, mid_y, strokeColor=C_TEXT, strokeWidth=1))
        d.add(Line(px, mid_y, cx, mid_y, strokeColor=C_TEXT, strokeWidth=1))
        d.add(Line(cx, mid_y, cx, cy, strokeColor=C_TEXT, strokeWidth=1))

    # Gen I
    draw_male(90, 160, affected=True)
    draw_female(190, 160, affected=False)
    couple_line(106, 160, 174, 160)
    d.add(String(140, 162, "x", fontSize=10, fontName="Helvetica-Bold",
                 fillColor=C_TEXT, textAnchor="middle"))
    d.add(String(60, 170, "Gen I", fontSize=8, fontName="Helvetica-Bold",
                 fillColor=C_HDR))

    # Gen II  - 4 children
    children = [(60, 80, True), (130, 80, False), (200, 80, True), (270, 80, False)]
    cx_mid = (90 + 190) / 2  # 140
    d.add(Line(cx_mid, 144, cx_mid, 120, strokeColor=C_TEXT, strokeWidth=1))
    d.add(Line(60, 120, 270, 120, strokeColor=C_TEXT, strokeWidth=1))
    for i, (cx, cy, aff) in enumerate(children):
        d.add(Line(cx, 120, cx, 96, strokeColor=C_TEXT, strokeWidth=1))
        if i % 2 == 0:
            draw_male(cx, cy, aff)
        else:
            draw_female(cx, cy, aff)
    d.add(String(30, 90, "Gen II", fontSize=8, fontName="Helvetica-Bold",
                 fillColor=C_HDR))

    # Legend
    d.add(Rect(30, 14, 20, 20, fillColor=colors.HexColor("#1565C0"),
               strokeColor=C_HDR, strokeWidth=1))
    d.add(String(55, 20, "Affected Male", fontSize=9, fontName="Helvetica", fillColor=C_TEXT))
    d.add(Rect(160, 14, 20, 20, fillColor=colors.HexColor("#90CAF9"),
               strokeColor=C_HDR, strokeWidth=1))
    d.add(String(185, 20, "Unaffected Male", fontSize=9, fontName="Helvetica", fillColor=C_TEXT))
    d.add(Circle(320, 24, 10, fillColor=colors.HexColor("#C62828"),
                 strokeColor=C_ACCENT, strokeWidth=1))
    d.add(String(335, 20, "Affected Female", fontSize=9, fontName="Helvetica", fillColor=C_TEXT))
    d.add(Circle(440, 24, 10, fillColor=colors.HexColor("#FFCDD2"),
                 strokeColor=C_ACCENT, strokeWidth=1))
    d.add(String(455, 20, "Unaffected", fontSize=9, fontName="Helvetica", fillColor=C_TEXT))
    return d


# ── Diagram 4: Down Syndrome Karyotype (simplified) ──────────────────────────
def down_syndrome_diagram():
    d = Drawing(CW, 110)
    d.add(Rect(0, 0, CW, 110, fillColor=colors.HexColor("#FFF3E0"), strokeColor=None))
    d.add(String(CW/2, 97, "DOWN SYNDROME - Trisomy 21", fontSize=12,
                 fontName="Helvetica-Bold", fillColor=C_ACCENT, textAnchor="middle"))

    # Draw chr 21 x3 and others schematically
    chr_colors = {
        "1":  "#E57373", "2":  "#64B5F6", "3":  "#81C784",
        "21a":"#FFB300", "21b":"#FFB300", "21c":"#E53935",
    }
    labels = ["Chr 1","Chr 2","...","Chr 21","Chr 21","Chr 21 (EXTRA!)"]
    xs = [20, 90, 160, 230, 295, 360]
    widths = [45,45,30,45,45,60]
    highlight = [False,False,False,False,False,True]
    chr_col = ["#E57373","#64B5F6","#B0BEC5","#FFB300","#FFB300","#E53935"]

    for x, lbl, w, hl, col in zip(xs, labels, widths, highlight, chr_col):
        sw = 3 if hl else 1
        sc = C_ACCENT if hl else C_HDR
        # chromosome shape: two bands
        d.add(Rect(x, 48, w, 30, fillColor=colors.HexColor(col),
                   strokeColor=sc, strokeWidth=sw, rx=5, ry=5))
        d.add(Rect(x, 40, w, 8, fillColor=colors.HexColor(col),
                   strokeColor=sc, strokeWidth=sw, rx=2, ry=2))
        d.add(String(x+w/2, 30, lbl, fontSize=7,
                     fontName="Helvetica-Bold" if hl else "Helvetica",
                     fillColor=C_ACCENT if hl else C_TEXT, textAnchor="middle"))

    d.add(String(CW/2, 14,
                 "Karyotype: 47,XX,+21  or  47,XY,+21   |   Occurs due to Non-Disjunction in Meiosis",
                 fontSize=8, fontName="Helvetica", fillColor=C_TEXT, textAnchor="middle"))
    return d


# ── Diagram 5: Inborn Errors of Metabolism ───────────────────────────────────
def metabolism_diagram():
    d = Drawing(CW, 120)
    d.add(Rect(0, 0, CW, 120, fillColor=colors.HexColor("#E0F7FA"), strokeColor=None))
    d.add(String(CW/2, 107, "INBORN ERRORS OF METABOLISM - Concept", fontSize=11,
                 fontName="Helvetica-Bold", fillColor=C_TEAL, textAnchor="middle"))

    # Normal pathway
    steps = ["Substrate A", "Enzyme X", "Product B", "Product C"]
    sx = [30, 130, 230, 330]
    for i, (s, x) in enumerate(zip(steps, sx)):
        col = colors.HexColor("#00897B") if i==0 else (
              colors.HexColor("#E53935") if i==1 else colors.HexColor("#1565C0"))
        d.add(Rect(x, 72, 85, 28, fillColor=col, strokeColor=C_TEAL,
                   strokeWidth=1, rx=4, ry=4))
        d.add(String(x+42, 82, s, fontSize=8,
                     fontName="Helvetica-Bold", fillColor=C_WHITE, textAnchor="middle"))
        if i < 3:
            d.add(Line(x+85, 86, x+100, 86, strokeColor=C_TEXT, strokeWidth=2))
            d.add(Polygon([x+100, 86, x+94, 90, x+94, 82],
                          fillColor=C_TEXT, strokeColor=C_TEXT))

    # Block cross
    d.add(String(152, 65, "BLOCKED", fontSize=7, fontName="Helvetica-Bold",
                 fillColor=C_ACCENT, textAnchor="middle"))
    d.add(Line(140, 72, 165, 57, strokeColor=C_ACCENT, strokeWidth=2))
    d.add(Line(165, 72, 140, 57, strokeColor=C_ACCENT, strokeWidth=2))

    # Accumulation arrow
    d.add(Line(72, 72, 72, 50, strokeColor=C_ACCENT, strokeWidth=1.5))
    d.add(Polygon([72, 47, 68, 53, 76, 53], fillColor=C_ACCENT, strokeColor=C_ACCENT))
    d.add(String(72, 38, "Accumulates", fontSize=7, fontName="Helvetica-Bold",
                 fillColor=C_ACCENT, textAnchor="middle"))

    d.add(String(CW/2, 18,
                 "PKU: Phenylalanine accumulates (no PAH enzyme)   |   Galactosaemia: Galactose accumulates",
                 fontSize=8, fontName="Helvetica", fillColor=C_TEXT, textAnchor="middle"))
    d.add(String(CW/2, 6,
                 "Huntington: CAG repeat expansion  |  Haemochromatosis: Iron overload",
                 fontSize=8, fontName="Helvetica-Bold", fillColor=C_TEAL, textAnchor="middle"))
    return d


# ── Diagram 6: Genetic Testing Overview ──────────────────────────────────────
def genetic_testing_diagram():
    d = Drawing(CW, 130)
    d.add(Rect(0, 0, CW, 130, fillColor=colors.HexColor("#EDE7F6"), strokeColor=None))
    d.add(String(CW/2, 115, "TYPES OF GENETIC TESTING", fontSize=12,
                 fontName="Helvetica-Bold", fillColor=colors.HexColor("#4A148C"),
                 textAnchor="middle"))

    types = [
        ("Karyotyping", "#7B1FA2", "Chromosome\nnumber/structure"),
        ("DNA Sequencing", "#1565C0", "Mutations in\ngene sequence"),
        ("FISH", "#00695C", "Specific\nchromosome region"),
        ("PCR", "#E65100", "Amplify &\ndetect DNA"),
    ]
    bw = (CW - 40) / 4
    for i, (name, col, desc) in enumerate(types):
        bx = 20 + i * bw
        d.add(Rect(bx, 58, bw-8, 42, fillColor=colors.HexColor(col),
                   strokeColor=C_WHITE, strokeWidth=1.5, rx=6, ry=6))
        d.add(String(bx+(bw-8)/2, 73, name, fontSize=8,
                     fontName="Helvetica-Bold", fillColor=C_WHITE, textAnchor="middle"))
        # description below box
        for j, line in enumerate(desc.split("\n")):
            d.add(String(bx+(bw-8)/2, 48 - j*12, line, fontSize=7,
                         fontName="Helvetica", fillColor=C_TEXT, textAnchor="middle"))

    d.add(String(CW/2, 16,
                 "Prenatal: Amniocentesis  |  CVS  |  Ultrasound  |  Maternal serum screening",
                 fontSize=8, fontName="Helvetica-Bold",
                 fillColor=colors.HexColor("#4A148C"), textAnchor="middle"))
    d.add(String(CW/2, 4,
                 "Postnatal: Newborn screening (PKU, hypothyroidism, galactosaemia)",
                 fontSize=8, fontName="Helvetica", fillColor=C_TEXT, textAnchor="middle"))
    return d


# ── Diagram 7: Genetic Therapy ────────────────────────────────────────────────
def gene_therapy_diagram():
    d = Drawing(CW, 130)
    d.add(Rect(0, 0, CW, 130, fillColor=colors.HexColor("#E8F5E9"), strokeColor=None))
    d.add(String(CW/2, 115, "GENE THERAPY - How it works", fontSize=12,
                 fontName="Helvetica-Bold", fillColor=colors.HexColor("#1B5E20"),
                 textAnchor="middle"))

    steps = [
        ("Normal\nGene", "#2E7D32"),
        ("Vector\n(Virus/Plasmid)", "#1565C0"),
        ("Delivery\ninto Cell", "#6A1B9A"),
        ("Expression\nin Cell", "#C62828"),
    ]
    bw = (CW - 60) / 4
    for i, (name, col) in enumerate(steps):
        bx = 20 + i * (bw + 16)
        # box
        d.add(Rect(bx, 52, bw, 50, fillColor=colors.HexColor(col),
                   strokeColor=C_WHITE, strokeWidth=1.5, rx=8, ry=8))
        for j, line in enumerate(name.split("\n")):
            d.add(String(bx+bw/2, 82 - j*14, line, fontSize=8,
                         fontName="Helvetica-Bold", fillColor=C_WHITE, textAnchor="middle"))
        # arrow
        if i < 3:
            ax = bx + bw + 2
            d.add(Line(ax, 77, ax+12, 77, strokeColor=C_TEXT, strokeWidth=2))
            d.add(Polygon([ax+12, 77, ax+7, 81, ax+7, 73],
                          fillColor=C_TEXT, strokeColor=C_TEXT))
        # step num
        d.add(String(bx+bw/2, 46, f"Step {i+1}", fontSize=7,
                     fontName="Helvetica-Bold", fillColor=C_TEXT, textAnchor="middle"))

    d.add(String(CW/2, 22,
                 "In Vivo: directly into patient   |   Ex Vivo: cells removed, treated, returned",
                 fontSize=8, fontName="Helvetica-Bold",
                 fillColor=colors.HexColor("#1B5E20"), textAnchor="middle"))
    d.add(String(CW/2, 8,
                 "Vectors: Adenovirus, Retrovirus, Lentivirus, AAV, Liposomes",
                 fontSize=8, fontName="Helvetica", fillColor=C_TEXT, textAnchor="middle"))
    return d


# ═══════════════════════════════════════════════════════════════════════════════
#  BUILD CONTENT
# ═══════════════════════════════════════════════════════════════════════════════
story = []

# ── Cover / Title ─────────────────────────────────────────────────────────────
story.append(Spacer(1, 10))
story.append(ColorBox("GENETICS", TITLE_STYLE, C_HDR, CW, height=60, radius=12))
story.append(Spacer(1, 4))
story.append(ColorBox("Short Notes  |  Units 1, 2, 4 & 5  (Unit 3 Excluded)", UNIT_STYLE,
                       C_HDR_LIGHT, CW, height=36, radius=8))
story.append(Spacer(1, 10))
story.append(HRFlowable(width=CW, thickness=2, color=C_ACCENT))
story.append(Spacer(1, 10))

# ══════════════════════════════════════════════════════════════════════════════
#  UNIT 1
# ══════════════════════════════════════════════════════════════════════════════
story += unit_header("UNIT 1 - Genetics in Nursing Applications, Gene Structure, Chromosomal Aberrations & Patterns of Inheritance")

# 1.1 Genetics in Nursing
story += section_box("1.1 Genetics in Nursing Application", [
    "<b>Definition:</b> Genetics = study of genes, heredity and variation in living organisms.",
    "<b>Nursing roles:</b> Identify at-risk families, educate about genetic conditions, support genetic testing decisions, coordinate with genetic counselors.",
    "<b>Types of Genetic Disorders:</b>",
    "  • Single gene (Mendelian) - e.g. PKU, Sickle cell",
    "  • Chromosomal - e.g. Down syndrome, Turner's",
    "  • Multifactorial - e.g. Cleft palate, Diabetes",
    "  • Mitochondrial - passed via mother only",
    "<b>Family History:</b> 3-generation pedigree helps identify risk patterns.",
], bg=C_BLUE)

# Gene structure diagram
story.append(gene_structure_diagram())
story.append(Spacer(1, 8))

# 1.2 Characteristics & Structure of Genes
story += section_box("1.2 Characteristics & Structure of Genes", [
    "<b>Gene:</b> Segment of DNA that codes for a specific protein or functional RNA.",
    "<b>DNA:</b> Double-stranded helix; nucleotides = Sugar (Deoxyribose) + Phosphate + Base.",
    "<b>Bases:</b> A-T (Adenine-Thymine) and G-C (Guanine-Cytosine) pairing.",
    "<b>Chromosome:</b> Condensed DNA + histone proteins; humans have 46 chromosomes (23 pairs).",
    "<b>Allele:</b> Alternate forms of a gene at same locus.",
    "<b>Genotype:</b> Genetic makeup (e.g. AA, Aa, aa). <b>Phenotype:</b> Observable trait.",
    "<b>Homozygous:</b> Both alleles same (AA or aa). <b>Heterozygous:</b> Different alleles (Aa).",
    "<b>Locus:</b> Fixed position on chromosome where a gene is located.",
], bg=C_BLUE)

# 1.3 Chromosomal Aberration
story.append(chromosomal_aberration_diagram())
story.append(Spacer(1, 8))

story += section_box("1.3 Chromosomal Aberrations", [
    "<b>Numerical Aberrations:</b>",
    "  • <b>Aneuploidy:</b> Extra or missing single chromosome",
    "     - Monosomy (2n-1): e.g. Turner's syndrome 45,XO",
    "     - Trisomy (2n+1): e.g. Down (chr 21), Patau (chr 13), Edwards (chr 18)",
    "  • <b>Polyploidy:</b> Extra complete chromosome set (triploid, tetraploid)",
    "<b>Structural Aberrations:</b>",
    "  • <b>Deletion:</b> Loss of chromosome segment",
    "  • <b>Duplication:</b> Extra copy of a segment",
    "  • <b>Inversion:</b> Segment flipped 180°",
    "  • <b>Translocation:</b> Segment moves to another chromosome",
    "<b>Cause:</b> Non-disjunction during meiosis, environmental mutagens, radiation.",
], bg=C_YELLOW)

# 1.4 Patterns of Inheritance
story.append(inheritance_diagram())
story.append(Spacer(1, 8))

story += section_box("1.4 Patterns of Inheritance", [
    "<b>Autosomal Dominant (AD):</b> One mutant allele enough; each generation affected; 50% risk per child. e.g. Huntington's, Marfan's.",
    "<b>Autosomal Recessive (AR):</b> Two mutant alleles needed; parents are carriers; 25% risk. e.g. PKU, Sickle cell, CF.",
    "<b>X-Linked Dominant:</b> Gene on X chromosome; dominant; e.g. Vitamin D-resistant rickets.",
    "<b>X-Linked Recessive:</b> Males affected more; females carriers; e.g. Haemophilia, G6PD, Duchenne MD.",
    "<b>Y-Linked:</b> Father to all sons; e.g. Y chromosome infertility.",
    "<b>Mitochondrial:</b> Mother to all children; no paternal transmission; e.g. MELAS syndrome.",
    "<b>Codominance:</b> Both alleles expressed; e.g. AB blood group.",
    "<b>Incomplete Dominance:</b> Intermediate phenotype; e.g. sickle cell trait.",
], bg=C_GREEN)

story += hr()

# ══════════════════════════════════════════════════════════════════════════════
#  UNIT 2
# ══════════════════════════════════════════════════════════════════════════════
story += unit_header("UNIT 2 - Conditions Affecting the Mother")

# 2.1 Prenatal Testing
story += section_box("2.1 Prenatal Testing & Diagnosis", [
    "<b>Purpose:</b> Identify fetal genetic/structural abnormalities early in pregnancy.",
    "<b>1. Amniocentesis (15-20 weeks):</b> Amniotic fluid sample → karyotype, DNA analysis. Risk: ~0.5% miscarriage.",
    "<b>2. Chorionic Villus Sampling (CVS) (10-13 weeks):</b> Placental tissue sample → earlier diagnosis. Risk slightly higher than amniocentesis.",
    "<b>3. Maternal Serum Screening:</b>",
    "   • Triple test: AFP, hCG, Estriol",
    "   • Quad test: adds Inhibin A",
    "   • NIPT (Non-Invasive Prenatal Testing): Cell-free fetal DNA in maternal blood - detects trisomies",
    "<b>4. Ultrasound:</b> Nuchal translucency (11-14 wks), fetal anomaly scan (18-22 wks).",
    "<b>5. Preimplantation Genetic Diagnosis (PGD):</b> IVF embryo tested before implantation.",
], bg=C_BLUE)

story.append(genetic_testing_diagram())
story.append(Spacer(1, 8))

# 2.2 Infertility
story += section_box("2.2 Infertility", [
    "<b>Definition:</b> Inability to conceive after 12 months of regular unprotected intercourse.",
    "<b>Genetic causes in females:</b> Turner syndrome (45,XO), Premature ovarian failure (FMR1 mutation), PCOS.",
    "<b>Genetic causes in males:</b> Klinefelter (47,XXY) - azoospermia; Y chromosome microdeletions (AZF regions).",
    "<b>Investigations:</b> Karyotype, hormonal profile, semen analysis, genetic mutation testing.",
    "<b>Management:</b> ART (IVF/ICSI), donor gametes, PGD, surrogacy; Genetic counseling for couples.",
], bg=C_PURPLE)

# 2.3 Spontaneous Abortion
story += section_box("2.3 Spontaneous Abortion", [
    "<b>Definition:</b> Loss of pregnancy before 20 weeks gestation.",
    "<b>Incidence:</b> ~15-20% of clinically recognized pregnancies.",
    "<b>Genetic causes (most common ~50%):</b> Chromosomal abnormalities - trisomies most frequent (T16 most common in 1st trimester), monosomy X, triploidy.",
    "<b>Other causes:</b> Uterine anomalies, hormonal imbalance, thrombophilia, immunological, infections.",
    "<b>Types:</b> Threatened, Inevitable, Incomplete, Complete, Missed, Recurrent (3+ losses).",
    "<b>Nursing care:</b> Emotional support, explain genetic causes, refer for karyotyping, genetic counseling for recurrent abortions.",
], bg=C_ORANGE)

# 2.4 Neural Tube Defects
story += section_box("2.4 Neural Tube Defects (NTDs)", [
    "<b>Definition:</b> Failure of neural tube to close during 3rd-4th week of fetal development.",
    "<b>Types:</b>",
    "  • <b>Spina Bifida:</b> Incomplete closure of spinal column",
    "     - Spina bifida occulta (hidden, minor)",
    "     - Meningocele (meninges protrude)",
    "     - Myelomeningocele (most severe - spinal cord + meninges protrude)",
    "  • <b>Anencephaly:</b> Absence of brain + skull vault - incompatible with life",
    "  • <b>Encephalocele:</b> Brain tissue protrudes through skull",
    "<b>Risk factors:</b> Folic acid deficiency, valproate use, diabetes, family history.",
    "<b>Prevention:</b> Folic acid 400 mcg/day pre-conception and first trimester (4 mg if previous NTD).",
    "<b>Diagnosis:</b> Maternal AFP elevated, ultrasound, amniocentesis.",
], bg=C_BLUE)

# 2.5 Down Syndrome
story.append(down_syndrome_diagram())
story.append(Spacer(1, 8))

story += section_box("2.5 Down Syndrome (Trisomy 21)", [
    "<b>Definition:</b> Chromosomal disorder due to extra copy of chromosome 21 (47 chromosomes).",
    "<b>Incidence:</b> 1 in 700 live births; increases with maternal age.",
    "<b>Cause:</b> Non-disjunction in meiosis (95%); Translocation (4%); Mosaicism (1%).",
    "<b>Features:</b> Flat facial profile, upslanting palpebral fissures, epicanthal folds, single palmar crease, hypotonia, intellectual disability.",
    "<b>Associated conditions:</b> Congenital heart defects (40%), GI anomalies, hypothyroidism, Alzheimer's (early onset), leukemia.",
    "<b>Diagnosis:</b> Karyotype (gold standard), NIPT, amniocentesis, CVS.",
    "<b>Nursing care:</b> Early intervention programs, developmental support, family education, support groups.",
], bg=C_ORANGE)

story += hr()

# ══════════════════════════════════════════════════════════════════════════════
#  UNIT 4
# ══════════════════════════════════════════════════════════════════════════════
story += unit_header("UNIT 4 - Inborn Errors of Metabolism, Huntington's Disease & Genetic Haemochromatosis")

# Metabolism diagram
story.append(metabolism_diagram())
story.append(Spacer(1, 8))

# 4.1 Inborn Errors of Metabolism
story += section_box("4.1 Inborn Errors of Metabolism (IEM)", [
    "<b>Definition:</b> Inherited disorders where a specific enzyme is absent/non-functional → substrate accumulates / product deficit.",
    "<b>Inheritance:</b> Mostly autosomal recessive.",
    "<b>Common examples:</b>",
    "  • <b>Phenylketonuria (PKU):</b> Phenylalanine hydroxylase (PAH) deficiency → phenylalanine accumulates → intellectual disability. Tx: Low-phenylalanine diet.",
    "  • <b>Galactosaemia:</b> GALT enzyme deficiency → galactose accumulates → jaundice, liver failure. Tx: Galactose-free diet.",
    "  • <b>MSUD (Maple Syrup Urine Disease):</b> BCAA metabolism defect → sweet-smelling urine, encephalopathy.",
    "  • <b>Gaucher Disease:</b> Glucocerebrosidase deficiency → glucocerebroside accumulates in liver/spleen/bone.",
    "  • <b>Pompe Disease:</b> Acid alpha-glucosidase deficiency → glycogen accumulates → cardiomyopathy.",
    "<b>Diagnosis:</b> Newborn screening (tandem mass spectrometry), enzyme assay, DNA analysis.",
    "<b>Nursing:</b> Monitor diet compliance, developmental milestones, metabolic crises.",
], bg=C_BLUE)

# 4.2 Huntington's Disease
story += section_box("4.2 Huntington's Disease (HD)", [
    "<b>Definition:</b> Progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansion in HTT gene (chromosome 4).",
    "<b>Inheritance:</b> Autosomal Dominant; 100% penetrance if mutation present.",
    "<b>Normal repeats:</b> <36 CAG | <b>HD:</b> ≥40 CAG repeats | Intermediate: 36-39.",
    "<b>Features (onset usually 30-50 yrs):</b>",
    "  • <b>Motor:</b> Chorea (involuntary jerking), dystonia, rigidity, falls",
    "  • <b>Cognitive:</b> Dementia, memory loss, poor planning",
    "  • <b>Psychiatric:</b> Depression, OCD, psychosis",
    "<b>Pathology:</b> Striatal (caudate + putamen) neuronal death.",
    "<b>Diagnosis:</b> DNA test (CAG repeat count). Presymptomatic testing possible with counseling.",
    "<b>Management:</b> No cure - symptomatic; Tetrabenazine (chorea), antidepressants, physiotherapy, speech therapy.",
    "<b>Nursing:</b> Safety measures (falls), nutritional support (high calorie), communication aids, end-of-life care.",
], bg=C_YELLOW)

# 4.3 Genetic Haemochromatosis
story += section_box("4.3 Genetic (Hereditary) Haemochromatosis (HH)", [
    "<b>Definition:</b> Autosomal recessive disorder of iron overload due to mutations in HFE gene (C282Y, H63D).",
    "<b>Mechanism:</b> Excess iron absorption from gut → iron deposits in liver, heart, pancreas, joints, skin.",
    "<b>Features:</b> Liver cirrhosis, hepatocellular carcinoma, diabetes ('bronze diabetes'), cardiomyopathy, arthropathy, hypogonadism, bronze skin discolouration.",
    "<b>Diagnosis:</b> Transferrin saturation >45%, serum ferritin elevated, HFE gene testing, liver biopsy.",
    "<b>Screening:</b> First-degree relatives of affected individuals.",
    "<b>Treatment:</b> Phlebotomy (venesection) - 500 mL blood/week until ferritin <50 μg/L, then maintenance. Chelation (deferoxamine) if phlebotomy contraindicated.",
    "<b>Nursing:</b> Monitor ferritin/iron studies, educate on diet (avoid iron supplements, vitamin C with meals), encourage compliance with venesection.",
], bg=C_GREEN)

story += hr()

# ══════════════════════════════════════════════════════════════════════════════
#  UNIT 5
# ══════════════════════════════════════════════════════════════════════════════
story += unit_header("UNIT 5 - Genetic Testing, Genetic Therapy & Genetic Counseling")

# 5.1 Genetic Testing
story += section_box("5.1 Genetic Testing", [
    "<b>Definition:</b> Analysis of chromosomes, DNA, RNA, proteins, or metabolites to detect genetic variants.",
    "<b>Types:</b>",
    "  • <b>Diagnostic testing:</b> Confirms/rules out a suspected genetic condition.",
    "  • <b>Predictive testing:</b> Identifies risk before symptoms (e.g. BRCA1/2 for breast cancer, HTT for HD).",
    "  • <b>Carrier testing:</b> Detects carriers of AR conditions (e.g. CF, sickle cell).",
    "  • <b>Prenatal testing:</b> Amniocentesis, CVS, NIPT, ultrasound.",
    "  • <b>Newborn screening:</b> Early detection (PKU, congenital hypothyroidism, galactosaemia).",
    "  • <b>Pharmacogenomics:</b> Genetic variants affecting drug response/metabolism.",
    "<b>Methods:</b> Karyotyping, FISH, PCR, DNA sequencing (Sanger, NGS), microarray.",
    "<b>Ethical issues:</b> Confidentiality, informed consent, insurance discrimination, psychological impact.",
], bg=C_PURPLE)

# 5.2 Gene Therapy
story.append(gene_therapy_diagram())
story.append(Spacer(1, 8))

story += section_box("5.2 Genetic Therapy (Gene Therapy)", [
    "<b>Definition:</b> Introduction, alteration, or replacement of genetic material within a cell to treat disease.",
    "<b>Types:</b>",
    "  • <b>Somatic gene therapy:</b> Targets non-reproductive cells; changes not inherited.",
    "  • <b>Germline gene therapy:</b> Targets reproductive cells; changes heritable (ethically controversial).",
    "  • <b>Gene replacement:</b> Replace faulty gene with normal copy.",
    "  • <b>Gene silencing:</b> Suppress overactive/harmful gene (e.g. RNAi, antisense oligonucleotides).",
    "  • <b>Gene editing (CRISPR-Cas9):</b> Precise cut and edit at specific DNA location.",
    "<b>Delivery (vectors):</b> Viral (adenovirus, AAV, retrovirus, lentivirus); Non-viral (liposomes, nanoparticles).",
    "<b>In vivo:</b> Gene delivered directly into patient's body.",
    "<b>Ex vivo:</b> Patient's cells removed, modified in lab, re-infused.",
    "<b>Examples:</b> Luxturna (RPE65 mutation - blindness), Zolgensma (SMA), CAR-T cell therapy.",
    "<b>Challenges:</b> Immune reactions, insertional mutagenesis, delivery efficiency, cost.",
], bg=C_ORANGE)

# 5.3 Genetic Counseling
story += section_box("5.3 Genetic Counseling", [
    "<b>Definition:</b> Process of providing individuals/families with information about genetic conditions, risks, testing options and decision support.",
    "<b>Goals:</b> Educate, empower, support non-directive decision making, reduce anxiety, improve outcomes.",
    "<b>Indications:</b>",
    "  • Advanced maternal age (≥35 years)",
    "  • Previous child with genetic disorder",
    "  • Family history of hereditary disease",
    "  • Consanguinity (related parents)",
    "  • Recurrent miscarriages",
    "  • Abnormal prenatal screen results",
    "<b>Process:</b> Risk assessment → Information giving → Discuss options → Psychological support → Follow-up.",
    "<b>Principles:</b> Non-directive, confidentiality, informed consent, autonomy.",
    "<b>Nurse's role:</b> Identify at-risk patients, initiate referral, provide pre/post-test counseling, emotional support, document accurately.",
    "<b>Ethical considerations:</b> Right not to know, duty to warn relatives, privacy vs. family disclosure.",
], bg=C_BLUE)

# ── Quick Reference Summary Table ────────────────────────────────────────────
story.append(Spacer(1, 6))
story += hr()
story.append(ColorBox("QUICK REFERENCE SUMMARY", UNIT_STYLE, C_ACCENT, CW, height=36, radius=6))
story.append(Spacer(1, 6))

summary_data = [
    [Paragraph("<b>Topic</b>", SUBHD_STYLE),
     Paragraph("<b>Key Point</b>", SUBHD_STYLE)],
    [Paragraph("Down Syndrome", BODY_STYLE),
     Paragraph("Trisomy 21 | Non-disjunction | 47 chromosomes | Flat face, hypotonia, IDD", BODY_STYLE)],
    [Paragraph("NTD Prevention", BODY_STYLE),
     Paragraph("Folic acid 400 mcg/day pre-conception | High AFP on maternal screen", BODY_STYLE)],
    [Paragraph("Huntington's", BODY_STYLE),
     Paragraph("AD | CAG repeat ≥40 | Chr 4 | Chorea, dementia | No cure", BODY_STYLE)],
    [Paragraph("Haemochromatosis", BODY_STYLE),
     Paragraph("AR | HFE gene | Iron overload | Tx: venesection | Bronze diabetes", BODY_STYLE)],
    [Paragraph("PKU", BODY_STYLE),
     Paragraph("AR | PAH deficiency | Phenylalanine ↑ | Tx: Low-phe diet | Newborn screen", BODY_STYLE)],
    [Paragraph("Gene Therapy", BODY_STYLE),
     Paragraph("Somatic (not heritable) vs Germline | CRISPR, viral vectors | In vivo / Ex vivo", BODY_STYLE)],
    [Paragraph("Genetic Counseling", BODY_STYLE),
     Paragraph("Non-directive | Risk assessment | Informed consent | Support | Confidentiality", BODY_STYLE)],
]
t = Table(summary_data, colWidths=[CW*0.28, CW*0.72])
t.setStyle(TableStyle([
    ('BACKGROUND', (0,0), (-1,0), C_HDR),
    ('TEXTCOLOR',  (0,0), (-1,0), C_WHITE),
    ('BACKGROUND', (0,1), (-1,-1), C_YELLOW),
    ('ROWBACKGROUNDS', (0,1), (-1,-1), [C_YELLOW, C_GREEN]),
    ('BOX',        (0,0), (-1,-1), 1.5, C_HDR_LIGHT),
    ('INNERGRID',  (0,0), (-1,-1), 0.5, colors.HexColor("#9FA8DA")),
    ('TOPPADDING',    (0,0), (-1,-1), 7),
    ('BOTTOMPADDING', (0,0), (-1,-1), 7),
    ('LEFTPADDING',   (0,0), (-1,-1), 8),
    ('VALIGN',     (0,0), (-1,-1), 'MIDDLE'),
]))
story.append(t)
story.append(Spacer(1, 10))

# Footer note
story.append(Paragraph(
    "<b>Note:</b> Unit 3 excluded as per instruction. These notes cover Units 1, 2, 4 & 5 only.",
    NOTE_STYLE))

# ─── Build ────────────────────────────────────────────────────────────────────
doc.build(story)
print("PDF created successfully!")